Thieno-pyrrole compounds as antagonists of gonadotropin releasing hormone

ABSTRACT

The invention relates to a group of novel thieno-pyrrole compounds of Formula (I), wherein: R 1 , R 2 , R 4 , R 5 , R 6 , R 6a , R 7 , R 8 , A and B are as defined in the specification, which are useful as gonadotrophin releasing hormone antagonists. The invention also relates to pharmaceutical formulations of said compounds, methods of treatment using said compounds and to processes for the preparation of said compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Stage under 35 U.S.C § 371 ofInternational Application No. PCT/GB2003/003603, filed Aug. 18, 2003,which claims priority under 35 U.S.C. § 119(a)-(d) to European PatentApplication No. 02292076.3 filed on Aug. 21, 2002, the specification ofwhich is incorporated by reference herein.

The present invention relates to compounds which are antagonists ofgonadotropin releasing hormone (GnRH) activity. The invention alsorelates to pharmaceutical formulations, the use of a compound of thepresent invention in the manufacture of a medicament, a method oftherapeutic treatment using such a compound and processes for producingthe compounds.

Gonadotropin releasing hormone (GnRH) is a decapeptide that is secretedby the hypothalamus into the hypophyseal portal circulation in responseto neural and/or chemical stimuli, causing the biosynthesis and releaseof luteinizing hormone (LH) and follicle-stimulating hormone (FSH) bythe pituitary. GnRH is also known by other names, includinggonadoliberin, LH releasing hormone (LHRH), FSH releasing hormone (FSHRH) and LH/FSH releasing factor (LH/FSH RP).

GnRH plays an important role in regulating the action of LH and FSH (byregulation of their levels), and thus has a role in regulating thelevels of gonadal steroids in both sexes, including the sex hormonesprogesterone, oestrogens and androgens. More discussion of GnRH can befound in WO 98/5519 and WO 97/14697, the disclosures of which areincorporated herein by reference.

It is believed that several diseases would benefit from the regulationof GnRH activity, in particular by antagonising such activity. Theseinclude sex hormone related conditions such as sex hormone dependentcancer, benign prostatic hypertrophy and myoma of the uterus. Examplesof sex hormone dependent cancers are prostatic cancer, uterine cancer,breast cancer and pituitary gonadotrophe adenoma.

The following disclose compounds purported to act as GNRH antagonists:WO 97/21435, WO 97/21703, WO 97/21704, WO 97/21707, WO 55116, WO98/55119, WO 98/55123, WO 98/55470, WO 98/55479, WO 99/21553, WO99/21557, WO 99/41251, WO 99/41252, WO 00/04013, WO 00/69433, WO99/51231, WO 99/51232, WO 99/51233, WO 99/51234, WO 99/51595, WO99/51596, WO 00/53178, WO 00/53180, WO 00/53179, WO 00/53181, WO00/53185, WO 00/53602, WO 02/066477, WO 02/666478, WO 02/06645 and WO02/092565.

It would be desirable to provide further compounds, such compounds beingGnRH antagonists. Thus, according to the first aspect of the inventionthere is provided a compound of Formula (I),

wherein

-   A represents a direct bond or optionally substituted C₁₋₅alkylene;-   B is a group of Formula (II):

-    wherein at position (a) Formula (II) is attached to the nitrogen    atom and the group X is attached to R⁸;-   R¹ represents hydrogen; optionally substituted C₁₋₈alkyl; or    (CH₂)_(b)—R^(a), wherein R^(a) represents C₃₋₈cycloalkyl and b is    zero or an integer from 1 to 6;-   R² represents an optionally substituted mono- or bi-cyclic aromatic    ring structure wherein the optional substituents are selected from    cyano, NR³R^(3a), optionally substituted C₁₋₈alkyl, optionally    substituted C₁₋₈alkoxy or halo;-   R³ and R^(3a) are independently selected from hydrogen; optionally    substituted C₁₋₈alkyl and optionally substituted aryl;-   R⁴ is hydrogen;-   R⁵ is selected from an optionally substituted 3- to 8-membered    heterocyclic ring containing from 1 to 4 heteroatoms independently    selected from O, N and S; or a group of formula III-a; III-b; III-c;    III-d; III-e; III-f, III-g, III-h, III-i, III-j, III-k or III-l;

-    wherein het represents an optionally substituted 3- to 8-membered    heterocyclic ring containing from 1 to 4 heteroatoms independently    selected from O, N and S;-   R⁶ and R^(6a), are independently selected from hydrogen and    optionally substituted C₁₋₈alkyl; or R⁶ and R^(6a) together    represent carbonyl;-   R⁷ represents hydrogen or optionally substituted C₁₋₈alkyl; or

-    together form an optionally substituted 3- to 8-membered    heterocyclic ring containing from 1 to 3 further heteroatoms    independently selected from O, N and S, and R^(6a) represents    hydrogen and optionally substituted C₁₋₈alkyl;-   X and R⁸ are selected from:    -   (i) X represents N and R⁸ is selected from:        -   cyano, hydrogen, hydroxy, —O—R^(b), —C(O)—R^(b),            —NR^(b)R^(c)—C(O)O—R^(b), —CONR^(b)R^(c) or NH—C(O)—R^(b),            where R^(b) and R^(c) are independently selected from            hydrogen and C₁₋₄alkyl optionally substituted with hydroxy,            amino, N—C₁₋₄alkylamino, N,N-di-C₁₋₄alkylamino,            HO—C₂₋₄alkyl-NH— or HO—C₂₋₄alkyl-N(C₁₋₄alkyl)-;    -   (ii) X represents CH and R⁸ represents NO₂; and    -   (iii) ═X—R⁸ together represent ═O;-   R¹¹ is a group of the formula: N(R⁹R¹⁰) wherein R⁹ represents    hydrogen, optionally substituted aryl, an optionally substituted 3-    to 10 membered heterocyclic ring or optionally-substituted C₁₋₈alkyl    and R¹⁰ represents hydrogen or optionally substituted C₁₋₈alkyl; or    the structure N(R⁹R¹⁰) represents an optionally-substituted 3- to 10    membered heterocyclic ring optionally containing from 1 to 3 further    heteroatoms independently selected from O, N and S;-   R¹² and R^(12a) are independently selected from hydrogen or    optionally substituted C₁₋₈alkyl; or R¹² and R^(12a) together with    the carbon to which they are attached form an optionally substituted    3 to 7-membered cycloalkyl ring;-   R¹³ and R¹⁴ are selected from:    -   (i) R¹³ is selected from hydrogen; optionally substituted        C₁₋₈alkyl; optionally substituted aryl; —R^(d)—Ar, where R^(d)        represents C₁₋₈alkylene and Ar represents optionally substituted        aryl; and optionally substituted 3- to 8-membered heterocyclic        ring optionally containing from 1 to 3 further heteroatoms        independently selected from O, N and S; and R¹⁴ is selected from        hydrogen; optionally substituted C₁₋₈alkyl and optionally        substituted aryl;    -   (ii) where R⁵ represents a group of formula III-a , III-b, III-i        or III-k, then the group NR¹³(—R¹⁴) represents an optionally        substituted 3- to 8-membered heterocyclic ring optionally        containing from 1 to 3 further heteroatoms independently        selected from O, N and S; or    -   (iii) where R⁵ represents structure III-e, then the group

-    represents an optionally substituted 3- to 8-membered heterocyclic    ring optionally containing from 1 to 4 heteroatoms independently    selected from O, N and S;-   R¹⁷ is selected from: hydrogen and C₁₋₄alkyl;-   or a salt, pro-drug or solvate thereof.

According to a further feature of the first aspect of the inventionthere is provided a compound of Formula (Ia),

wherein

-   A represents a direct bond or optionally substituted C₁₋₅alkylene;-   B is a group of Formula (II):

-    wherein at position (a) Formula (II) is attached to the nitrogen    atom and the group X is attached to R⁸;-   R¹ represents hydrogen; optionally substituted C₁₋₈alkyl; or    (CH₂)_(b)—R^(a), wherein R^(a) represents C₃₋₈cycloalkyl and b is    zero or an integer from 1 to 6;-   R² represents an optionally substituted mono- or bi-cyclic aromatic    ring structure wherein the optional substituents are selected from    cyano, NR³R^(3a), optionally substituted C₁₋₈alkyl, optionally    substituted C₁₋₈alkoxy or halo;-   R³ and R^(3a) are independently selected from hydrogen; optionally    substituted C₁₋₈alkyl and optionally substituted aryl;-   R⁴ is hydrogen;-   R⁵ is selected from an optionally substituted 3- to 8-membered    heterocyclic ring containing from 1 to 4 heteroatoms independently    selected from O, N and S; or a group of formula III-a; III-b; III-c;    III-d; III-e; III-f, III-g, III-h, III-i or: III-j;

-    wherein het represents an optionally substituted 3- to 8-membered    heterocyclic ring containing from 1 to 4 heteroatoms independently    selected from O, N and S;-   R⁶ and R^(6a), are independently selected from hydrogen and    optionally substituted C₁₋₈alkyl; or R⁶ and R^(6a) together    represent carbonyl;-   R⁷ represents hydrogen or optionally substituted C₁₋₈alkyl; or

-    together form an optionally substituted 3- to 8-membered    heterocyclic ring containing from 1 to 3 further heteroatoms    independently selected from O, N and S, and R^(6a) represents    hydrogen and optionally substituted C₁₋₈alkyl;-   X and R⁸ are selected from:    -   (i) X represents N and R⁸ is selected from:        -   cyano, hydrogen, hydroxy, —O—R^(b),            —NR^(b)R^(c)—C(O)O—R^(b), —CONR^(b)R^(c) or NH—C(O)—R^(b),            where R^(b) and R^(c) are independently selected from            hydrogen and C₁₋₄alkyl optionally substituted with hydroxy,            amino, N—C₁₋₄alkylamino, N,N-di-C₁₋₄alkylamino,            HO—C₂₋₄alkyl-NH— or HO—C₂₋₄alkyl-N(C₁₋₄alkyl)-;    -   (ii) X represents CH and R⁸ represents NO₂; and    -   (iii) X—R⁸ together represent —O—;-   R¹¹ is a group of the formula: N(R⁹R¹⁰) wherein R⁹ represents    hydrogen, aryl, an optionally substituted 3- to 10 membered    heterocyclic ring or optionally-substituted C₁₋₈alkyl and R¹⁰    represents hydrogen or optionally substituted C₁₋₈alkyl; or the    structure N(R⁹R¹⁰) represents an optionally-substituted 3- to 10    membered heterocyclic ring optionally containing from 1 to 3 further    heteroatoms independently selected from O, N and S;-   R¹² and R^(12a) are independently selected from hydrogen or    optionally substituted C₁₋₈alkyl; or R¹² and R^(12a) together with    the carbon to which they are attached form an optionally substituted    3 to 7-membered cycloalkyl ring;-   R¹³ and R¹⁴ are selected from:    -   (i) R¹³ is selected from hydrogen; optionally substituted        C₁₋₈alkyl; optionally substituted aryl; —R^(d)—Ar, where R^(d)        represents C₁₋₈alkylene and Ar represents optionally substituted        aryl; and optionally substituted 3- to 8-membered heterocyclic        ring optionally containing from 1 to 3 further heteroatoms        independently selected from O, N and S; and R¹⁴ is selected from        hydrogen; optionally substituted C₁₋₈alkyl and optionally        substituted aryl;    -   (ii) where R⁵ represents a group of formula III-a, III-b or        III-i, then the group NR¹³(—R¹⁴) represents an optionally        substituted 3- to 8-membered heterocyclic ring optionally        containing from 1 to 3 further heteroatoms independently        selected from O, N and S; or    -   (iii) where R⁵ represents structure III-e, then the group

-    represents an optionally substituted 3- to 8-membered heterocyclic    ring optionally containing from 1 to 4 heteroatoms independently    selected from O, N and S;-   or a salt, pro-drug or solvate thereof.

According to a further feature of the first aspect of the inventionthere is provided a pharmaceutical formulation comprising a compound ofFormula (I) or Formula (Ia), or salt, pro-drug or solvate thereof, and apharmaceutically acceptable diluent or carrier.

According to a further feature of the first aspect of the inventionthere is provided the following uses of a compound of a compound ofFormula (I) or Formula (Ia), or salt, pro-drug or solvate thereof:

-   (a) the use in the manufacture of a medicament for antagonising    gonadotropin releasing hormone activity;-   (b) the use in the manufacture of a medicament for administration to    a patient, for reducing the secretion of luteinizing hormone by the    pituitary gland of the patient; and-   (c) the use in the manufacture of a medicament for administration to    a patient, for therapeutically treating and/or preventing a sex    hormone related condition in the patient, preferably a sex hormone    related condition selected from prostate cancer and pre-menopausal    breast cancer.

According to a further aspect of the invention there is provided amethod of antagonising gonadotropin releasing hormone activity in apatient, comprising administering a compound of Formula (I) or Formula(Ia), or salt, prodrug or solvate thereof, to a patient.

Whilst pharmaceutically-acceptable salts of compounds of the inventionare preferred, other non-pharmaceutically-acceptable salts of compoundsof the invention may also be useful, for example in the preparation ofpharmaceutically-acceptable salts of compounds of the invention.

Whilst the invention comprises compounds of the invention, and salts,pro-drugs or solvates thereof, in a further embodiment of the invention,the invention comprises compounds of the invention and salts thereof.

In the present specification, unless otherwise indicated, an alkyl,alkylene or alkenyl moiety may be linear or branched.

The term “alkylene” refers to the group —CH₂—. Thus, C₈ alkylene forexample is —(CH₂)₈—.

The term “aryl” refers to phenyl or naphthyl.

The term “carbamoyl” refers to the group —CONH₂.

The term “halo” refers to fluoro, chloro, bromo or iodo.

The term “heterocyclyl” or “heterocyclic ring” refers to a 4-12membered, preferably 5-10 membered aromatic mono or bicyclic ring or a4-12 membered, preferably 5-10 membered saturated or partially saturatedmono or bicyclic ring, said aromatic, saturated or partially unsaturatedrings containing up to 5 heteroatoms independently selected fromnitrogen, oxygen or sulphur, linked via ring carbon atoms or ringnitrogen atoms where a bond from a nitrogen is allowed, for example nobond is possible to the nitrogen of a pyridine ring, but a bond ispossible through the 1-nitrogen of a pyrazole ring. Examples of 5- or6-membered aromatic heterocyclic rings include pyrrolyl, furanyl,imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl,isoxazolyl, oxazolyl, 1,2,4 oxadiazolyl, isothiazolyl, thiazolyl andthienyl. A 9 or 10 membered bicyclic aromatic heterocyclic ring is anaromatic bicyclic ring system comprising a 6-membered ring fused toeither a 5 membered ring or another 6 membered ring. Examples of 5/6 and6/6 bicyclic ring systems include benzofuranyl, benzimidazolyl,benzthiophenyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl,benzisoxazolyl, indolyl, pyridoimidazolyl, pyrimidoimidazolyl,quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl,cinnolinyl and naphthyridinyl. Examples of saturated or partiallysaturated heterocyclic rings include pyrrolinyl, pyrrolidinyl,morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl anddihydropyrimidinyl. This definition further comprises sulphur-containingrings wherein the sulphur atom has been oxidised to an S(O) or S(O2)group.

The term “aromatic ring” refers to a 5-10 membered aromatic mono orbicyclic ring optionally containing up to 5 heteroatoms independentlyselected from nitrogen, oxygen or sulphur. Examples of such “aromaticrings” include: phenyl, pyrrolyl, furanyl, imidazolyl, triazolyl,pyrazinyl, pyriminyl, pyridazinyl, pyridinyl, isoxazolyl, oxazolyl,1,2,4 oxadiazolyl, isothiazolyl, thiazolyl and thienyl. Preferredaromatic rings include 'phenyl, thienyl and pyridyl.

The symbol

denotes where the respective group is linked to the remainder of themolecule.

For the avoidance of doubt, when

together form an optionally substituted 3- to 8-membered heterocyclicring containing from 1 to 3 further heteroatoms independently selectedfrom O, N and S, then the groups shown cyclise to form anitrogen-containing heterocyclic ring, i.e

optionally containing from 1 to 3 further heteroatoms independentlyselected from O, N and S.

Examples of C₁₋₈alkyl include: methyl, ethyl, propyl, isopropyl, butyl,iso-butyl, tert-butyl and 2-methyl-pentyl; example of C₁₋₈alkyleneinclude: methylene, ethylene and 2-methyl-propylene; examples ofC₁₋₈alkoxy include methoxy, ethoxy and butyloxy; examples ofN—C₁₋₄alkylamino include N-methylamino and N-ethylamino; examples ofN,N-di-C₁₋₄alkylamino, examples of HO—C₂₋₄alkyl-NH includehydroxymethylamino hydroxyethylamino and hydroxypropyamino, examples ofHO—C₂₋₄alkyl-N(C₁₋₄alkyl) include N-methyl-hydroxymethylamino,N-ethyl-hydroxyethylamino, and N-propyl-hydroxypropyamino.

It is to be understood that, insofar as certain of the compounds of theinvention may exist in optically active or racemic forms by virtue ofone or more asymmetric carbon atoms, the invention includes in itsdefinition any such optically active or racemic form which possesses theproperty of antagonizing gonadotropin releasing hormone (GnRH) activity.The synthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Similarly, activity of these compounds may be evaluatedusing the standard laboratory techniques referred to hereinafter.

The invention also relates to any and all tautomeric forms of thecompounds of the different features of the invention that possess theproperty of antagonizing gonadotropin releasing hormone (GnRH) activity.

It will also be understood that certain compounds of the presentinvention may exist in solvated, for example hydrated, as well asunsolvated forms. It is to be understood that the present inventionencompasses all such solvated forms which possess the property ofantagonizing gonadotropin releasing hormone (GnRH) activity.

Preferred compounds of Formula (I) are those wherein any one of thefollowing or a combination of the following apply.

Preferably A represents optionally substituted C₁₋₅alkylene. Furtherpreferably C₁₋₄alkylene. Most preferably methylene or ethylene.

Preferably R¹ represents hydrogen or optionally substituted C₁₋₆alkyl.More preferably R¹ represents hydrogen or unsubstituted C₁₋₆alkyl. Yetmore preferably R¹ represents hydrogen, methyl, ethyl or tert-butyl.Most preferably R¹ represents hydrogen.

Preferably R² represents an optionally substituted monocyclic aromaticring structure wherein the optional substituents are selected fromcyano, NR^(e)R^(f), optionally substituted C₁₋₈alkyl (preferably,C₁₋₄alkyl, eg, methyl or ethyl), optionally substituted C₁₋₈alkoxy(preferably, C₁₋₆alkoxy, eg, methoxy, ethoxy or tert-butoxy) or halo(eg, F, Br or Cl) wherein R^(e) and R^(f) are independently selectedfrom hydrogen, C₁₋₆alkyl or aryl. Further preferably R² is optionallysubstituted phenyl wherein the optional substituents are selected fromcyano, NR^(e)R^(f), optionally substituted C₁₋₄alkyl, optionallysubstituted C₁₋₆alkoxy, F, Br or Cl wherein R^(e) and R^(f) are asdefined above. Yet further preferably R² is optionally substitutedphenyl wherein the optional substituents are selected from methyl,ethyl, methoxy, ethoxy, tert-butoxy, F or Cl. Most preferably R²represents

wherein Me represents methyl. Preferably R² bears 1, 2 or 3substituents.

Preferably R³ and R^(3a) are independently selected from hydrogen;optionally substituted C₁₋₆alkyl and, optionally substituted aryl.Further preferably R³ and R^(3a) are independently selected from methyl,ethyl, tert-butyl and phenyl.

Preferably R⁵ is selected from a group of formula III-a, III-g, III-h,III-i or III-j:

Further preferably R⁵ is selected from one of the following groups:

Yet further preferably R⁵ is selected from one of the following groups:

-   -   wherein Me represents methyl.

Yet further preferably R⁵ is selected from one of the following groups:

Most preferably R⁵ is:

Preferably R⁶ and R^(6a) are independently selected from hydrogen,fluoro or optionally substituted C₁₋₆alkyl. Preferably R⁶ and R^(6a) areindependently selected from hydrogen, fluoro and unsubstitutedC₁₋₆alkyl. Yet more preferably R⁶ and R^(6a) are independently selectedfrom hydrogen or methyl. Most preferably R⁶ is hydrogen and R^(6a) ismethyl.

In a further embodiment of the invention, R⁶ and R^(6a) each representhydrogen and A represents C₁₋₄alkylene (preferably methylene).

In a yet further embodiment of the invention R⁶ represents hydrogen,R^(6a) represents methyl, and A represents C₁₋₄alkylene (preferablymethylene).

Preferably R⁷ is selected from hydrogen or optionally-substitutedC₁₋₆alkyl. Further preferably R⁷ represents hydrogen, methyl, ethyl ortert-butyl). Most preferably R⁷ is hydrogen.

Preferably X and R⁸ are selected from:

-   (a) ═X—R⁸ represents ═O; or-   (b) X represents N and R⁸ represents hydrogen, hydroxy, cyano,    —O—R^(b), —C(O)—R^(b), —C(O)O—R^(b) and —C(O)NR^(b)R^(c); wherein    R^(b) and R^(c) are as defined above.

Further preferably X and R⁸ represent either:

-   (a) X represents N and R⁸ represents cyano or —C(O)O—R^(b); or-   (b) X represents N and R⁸ represents hydrogen.    Further preferably X and R⁸ represent either:-   (a) X represents N and R⁸ represents cyano or —C(O)O—R^(b); wherein    R^(b) represents C₁₋₆alkyl;    In a further embodiment of the invention X represents N and R⁸    represents —CONR^(b)R^(c) wherein R^(b) and R^(c) are as defined    above.

In a further embodiment of the invention the group ═X—R⁸ is selectedfrom:

-   (a) X represents N and R⁸ represents hydrogen, cyano, hydroxy,    —O—R^(b), —C(O)—R^(b), and —C(O)O—R^(b), wherein R^(b) is selected    from methyl, ethyl or isopropyl;-   (b) X represents N and R⁸ represents carbamoyl; and-   (c) ═X—R^(e) represents ═O.

In a further embodiment of the invention the group ═X—R⁸ is selectedfrom:

-   (a) X represents N and R⁸ represents hydrogen, cyano, hydroxy,    carbamoyl, acetyl, methoxy, methoxycarbonyl, ethoxycarbonyl or    isopropoxycarbonyl; and

(b) ═X—R⁸ represents ═O. In a further embodiment of the invention thegroup ═X—R⁸ is selected from:

-   (a) X represents N and R⁸ represents methoxycarbonyl, ethoxycarbonyl    or isopropoxycarbonyl; and-   (b) ═X—R⁸ represents ═O.

Preferably R⁹ comprises part of the optionally substituted heterocyclicring N(R⁹R¹⁰) or is hydrogen, optionally substituted aryl, an optionallysubstituted 3- to 10 membered heterocyclic ring or optionallysubstituted C₁₋₆alkyl, preferably C₁₋₄alkyl, wherein the optionalsubstituents are selected from: hydroxy, amino, nitro, cyano,optionally-substituted aryl, optionally substituted 3- to 8-memberedheterocyclyl containing from 1 to 4 heteroatoms independently selectedfrom O, N and S, —O—R^(b), C(O)NR^(b)R^(c), —NR^(b)R^(c),—NR^(c)C(O)—R^(b), —C(O)NR^(b)R^(c), —NR^(c)S(O₀₋₂)R^(b), —S(O₀₋₂)R^(b),wherein R^(b) and R^(c) are as defined above.

Further preferably R⁹ comprise part of the optionally substitutedheterocyclic ring N(R⁹R¹⁰) or is selected from optionally substitutedC₁₋₆alkyl.

Yet further preferably R⁹ comprise part of the optionally substitutedheterocyclic ring N(R⁹R¹⁰) or is selected from optionally subsitutedC₁₋₆alkyl, wherein the optional subsitutents are selected from: cyano oran optionally substituted 3 to 10 membered heterocyclic ring.

Yet further preferably R⁹ comprise part of the optionally substitutedheterocyclic ring N(R⁹R¹⁰).

When R⁹ is a C₁₋₆alkyl group substituted by an optionally-substituted 3to 10 membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from O, N and S, the heterocyclic ring ispreferably selected from pyridyl, thienyl, piperidinyl, imidazolyl,triazolyl, thiazolyl, pyrrolidinyl, piperazinyl, morpholinyl,imidazolinyl, benztriazolyl, benzimidazolyl, pyrimidinyl, pyrazinyl,pyridazinyl, oxazolyl, furanyl, pyrrolyl, 1,3-dioxolanyl, 2-azetinyl,each of which is optionally substituted, wherein the optionalsubstituents are preferably selected from R¹⁶. Further preferably agroup of formula VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i,VI-j or VI-k:, wherein each group is optionally substituted by one ormore groups selected from R¹⁶.

Further preferably a group of formula VI-b, VI-i, or VI-j:

wherein

-   R¹⁶ represents hydrogen, aryl, a 3- to 10 membered heterocyclic ring    or optionally substituted C₁₋₄alkyl wherein the optional    substituents are selected from: hydroxy, amino, nitro, cyano,    optionally-substituted phenyl, optionally substituted 3- to    8-membered heterocyclyl containing from 1 to 4 heteroatoms    independently selected from O, N and S, —O—R^(b), C(O)NR^(b)R^(c),    —NR^(b)R^(c), —NR^(c)C(O)—R^(b), —C(O)NR^(b)R^(c),    —NR^(c)S(O₀₋₂)R^(b), —S(O₀₋₂)R^(b), wherein R^(b) and R^(c) are as    defined above; Preferably R¹⁶ represents hydrogen or C₁₋₄alkyl    optionally substituted by hydroxy, amino, nitro or cyano. Most    preferably R¹⁶ represents hydrogen or methyl.

Most preferably when R⁹ is a C₁₋₆alkyl group substituted by anoptionally-substituted 3 to 10 membered heterocyclic ring containingfrom 1 to 4 heteroatoms independently selected from O, N and S, theheterocyclic ring is preferably selected piperazinyl, pyridyl orpyrrolyl, optionally substituted with methyl.

When R⁹ is a C₁₋₆alkyl group substituted by an optionally-substituted 3to 10 membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from O, N and S, the C₁₋₆alkyl group ispreferably selected from ethyl or propyl.

Preferably R¹⁰ comprises part of the group N(R⁹R¹⁰) or is optionallysubstituted C₁₋₆alkyl. Further preferably R¹⁰ comprises part of thegroup N(R⁹R¹⁰) or is selected from: methyl, ethyl or tert-butyl. Mostpreferably R¹⁰ comprises part of the group N(R⁹R¹⁰).

When N(⁹R¹⁰) represent an optionally substituted 3- to 10-memberedheterocyclic ring, N(R⁹R¹⁰) is preferably selected from a 5- or6-membered monocyclic ring containing between 1 and 3 (preferably 1 or2) heteroatom independently selected from O, N and S. Further preferablya 5- or 6-membered monocyclic ring containing between 1 and 3(preferably 1 or 2) heteroatom independently selected from O, N and Sselected from pyrrolidinyl, thienyl, pyrazolidinyl, piperidinyl,morpholinyl, thiomorpholinyl piperazinyl, imidazole, or azetidinyl.Further preferably the structure N(R⁹R¹⁰) is a heterocyclic ringselected from an optionally-substituted group of formula, IV-a, IV-b,IV-c, IV-d and IV-e, wherein the optional substituents are preferablyselected from the groups listed for R¹⁵ below

Further preferably the structure N(R⁹R¹⁰) is selected from a group offormula Va, Vb or Vc:

Most preferably the structure N(R⁹R¹⁰) is a group of formula V-a or V-c:

-   R¹⁵ represents the group R^(15a)-Z-    wherein:-   R^(15a) represents hydrogen, optionally substituted aryl, an    optionally substituted 3- to 10 membered heterocyclic ring or    optionally substituted C₁₋₄alkyl, wherein the optional substituents    are selected from: hydroxy, amino, nitro, cyano,    optionally-substituted aryl, optionally substituted 3- to 8-membered    heterocyclyl containing from 1 to 4 heteroatoms independently    selected from O, N and S, —O—R^(g), —C(O)—R^(g), —C(O)NR^(g)R^(h),    —NR^(g)R^(h), —NR^(h)C(O)—R^(g), —C(O)NR^(g)R^(h),    —NR^(h)S(O₀₋₂)R^(g), —S(O₀₋₂)R^(g), wherein R^(g) and R^(g) are    independently selected from: heterocyclyl, hydrogen and C₁₋₄alkyl    optionally substituted with hydroxy, amino, N—C₁₋₄alylamino,    N,N-di-C₁₋₄alkylamino, HO—C₂₋₄alkyl-NH— or    HO—C₂₋₄alkyl-N(C₁₋₄alkyl)-. Preferably R¹⁵ is heterocyclyl,    —C(O)-heterocyclyl or —(CH₂)₀₋₂—C(O)NR^(g)R^(h), wherein R^(g) and    R^(h) are independently selected from C₁₋₄alkyl or hydrogen; and-   Z is selected from: a direct bond, —(CH₂)_(s1)—,    —(CH₂)_(s1)—O—(CH₂)_(s2)—, —(CH₂)_(s1)—C(O)—(CH₂)_(s2)—,    —(CH₂)_(s1)—S(O_(n))—(CH₂)_(s2)—, —(CH₂)_(s1)—N(R¹⁸)—(CH₂)_(s2)—,    —(CH₂)_(s1)—C(O)N(R¹⁸)—(CH₂)_(s2)—,    —(CH₂)_(s1)—N(R¹⁸)C(O)—(CH₂)_(s2),    —(CH₂)_(s1)—N(R¹⁸)C(O)N(R¹⁸)—(CH₂)_(s2)—,    —(CH₂)_(s1)—OC(O)—(CH₂)_(s2)—, —(CH₂)_(s1)—C(O)O—(CH₂)_(s2)—,    —(CH₂)_(s1)—N(R¹⁸)C(O)O—(CH₂)_(s2)—,    —(CH₂)_(s1)—OC(O)N(R¹⁸)—(CH₂)_(s2)—,    —(CH₂)_(s1)—OS(O_(n))—(CH₂)_(s2)—, or    —(CH₂)_(s1)—S(O_(n))—O—(CH₂)_(s2)—,    —(CH₂)_(s1)—S(O)₂N(R¹⁸)—(CH₂)_(s2)—,    —(CH₂)_(s1)—N(R¹⁸)S(O)₂—(CH₂)_(s2)—; wherein the —(CH₂)_(s1)— and    —(CH₂)_(s2)— groups are independently optionally substituted by    hydroxy or C₁₋₄alkyl and s1 and s2 are independently an integer from    0 to 2, wherein s1+s2 is less than or equal to 2 and R¹⁸ is selected    from hydrogen or C₁₋₄alkyl (preferably hydrogen).

Preferred values for Z are selected from: —(CH₂)_(s1)—,—(CH₂)_(s1)—O—(CH₂)_(s2)—, —(CH₂)_(s1)—C(O)—, —C(O)—(CH₂)_(s2)—,—(CH₂)_(s1)—N(R¹⁸)—, —(CH₂)_(s1)—C(O)N(R¹⁸)—,—(CH₂)_(s1)—NR¹⁸)C(O)—(CH₂)_(s2)—, —(CH₂)_(s1)—S(O)₂—N(R¹⁸)— or—(CH₂)_(s1)—NHS(O)₂—, wherein s1 and s2 are independently selected from0,1, or 2 and s1+s2 is less than or equal to 2, R¹⁸ is selected fromhydrogen or C₁₋₄alkyl (preferably hydrogen) and the —(CH₂)_(s)— group isoptionally substituted by hydroxy or C₁₋₄alkyl.

Further preferred values for Z are selected from: a direct bond,methylene, ethylene, propylene, oxy, 2-hydroxypropylene, carbonyl,methylcarbonyl, ethylcarbonyl, (methyl)methylcarbonyl,(ethyl)methylcarbonyl, carbonylmethylene, carbonylethylene,ethoxyethylene, amino, 2-hydroxypropylamino, carbonylamino,methylcarbonylamino, aminocarbonyl, methylaminocarbonyl,methylaminocarbonylmethyl, propylsulphonylamino or methylaminosulphonyl

The most preferred values for Z are a direct bond or carbonyl.

Further preferably R¹⁵ is selected from: N-isopropylaminocarbonylmethyl,tetrahydropyranyl, morpholinocarbonyl, pyridyl, pyrazinyl, pyridazinyl,pyrimidinyl or thiazolyl.

Yet further preferably R¹⁵ is N-isopropylaminocarbonylmethyl,tetrahydropyranyl, morpholinocarbonyl or pyridyl.

Most preferably R¹⁵ is pyridyl.

In a further embodiment of the invention R¹⁵ represents hydrogen,optionally substituted aryl, an optionally substituted 3- to 10 memberedheterocyclic ring or optionally substituted C₁₋₄alkyl wherein theoptional substituents on aryl, a heterocyclic ring or C₁₋₄alkyl areselected from: hydroxy, amino, nitro, cyano, optionally-substitutedaryl, optionally substituted 3- to 8-membered heterocyclyl containingfrom 1 to 4 heteroatoms independently selected from O, N and S,—O—R^(b), C(O)NR^(b)R^(c), —NR^(b)R^(c), —NR^(c)C(O)—R^(b),—C(O)NR^(b)R^(c), —NR^(c)S(O₀₋₂)R^(b), —S(O₀₋₂)R^(b), wherein R^(b) andR^(c) are as defined above. Preferably R¹⁵ is heterocyclyl. Furtherpreferably R¹⁵ is selected from: pyridyl, pyrazinyl, pyridazinyl,tetrahydropyranyl, pyrimidinyl or thiazolyl. Most preferably R¹⁵ ispyridyl.

In a further embodiment of the invention N(R⁹R¹⁰) represent anoptionally substituted 3- to 10-membered heterocyclic ring, wherein theoptional substituents are selected from R¹⁵ as defined above.

Preferably R¹² and R^(12a) are independently selected from: hydrogen,optionally substituted C₁₋₆alkyl or R¹² and R^(12a) together with carbonto which they are attached from an optionally substituted 3- to6-membered cycloalkyl ring. Further preferably R¹² and R^(12a) areindependently selected from: hydrogen, methyl, ethyl or tert-butyl. Mostpreferably R¹² and R^(12a) are both methyl.

Preferably R¹³ and R¹⁴, are independently selected from hydrogen,optionally substituted C₁₋₆alkyl, optionally substituted phenyl and—R^(d)-phenyl, where R^(d) represents C₁₋₆alkylene or and an optionallysubstituted 3- to 8-membered heterocyclic ring (preferably, a 5- or6-membered monocyclic ring) containing from 1 to 3 (preferably 1 or 2)further heteroatoms independently selected from O, N and S. Furtherpreferably R¹³ and R¹⁴, are independently selected from hydrogen orC₁₋₆alkyl.

Where optional substitution is mentioned at various places, this refersto one, two, three or more optional substituents. Unless otherwiseindicated above (ie, where a list of optional substituents is provided),each substituent can be independently selected from C₁₋₈alkyl (eg,C₂₋₆alkyl, and most preferably methyl, ethyl or tert-butyl);C₃₋₈cycloalkoxy, preferably cyclopropoxy, cyclobutoxy or cyclopentoxy;C₁₋₆alkoxy, preferably methoxy or C₂₋₄alkoxy; halo, preferably Cl or F;Hal₃C—, Hal₂CH—, HalCH₂—, Hal₃CO—, Hal₂CHO or Hal CH₂O, wherein Halrepresents halo (preferably F); R^(g)CH₂O—, R^(h)C(O)N(R)—,R^(h)SO₂N(R)— or R^(g)—R^(h)N—, wherein R^(g) and R^(h) independentlyrepresent hydrogen or C₁₋₈alkyl (preferably methyl or C₂₋₆alkyl orC₂₋₄alkyl), or R^(g)—R^(h)N— represents an optionally substituted C₃₋₈,preferably C₃₋₆, heterocyclic ring optionally containing from 1 to 3further heteroatoms independently selected from O, N and S; hydrogen; orR^(k)C(O)O— or R^(k)C(O)—, R^(k) representing hydrogen, optionallysubstituted phenyl or C₁₋₆alkyl (preferably methyl, ethyl, iso-propyl ortert-butyl). For optional substitution of the heterocyclic ringrepresented by R^(g)—R^(h)N—, at least one (eg, one, two or three)substituents may be provided independently selected from C₁₋₆alkyl (eg,C₂₋₄alkyl, more preferably methyl); phenyl; CF₃O—; F₂CHO—; C₁₋₈alkoxy,preferably methoxy, ethoxy or C₃₋₆alkoxy; C₁₋₈alkoxyC(O), preferablymethoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or C₃₋₆alkoxyC(O)—;phenoxycarbonyl; phenoxy; C₁₋₈alkanoyl, preferably acetyl, ethanoyl orC₃₋₆alkyanoyl; carboxy; C₁₋₈alkylS(O)_(nn) wherein nn is an integerbetween 0 and 2, preferably methylthio, ethylthio, C₃₋₆alkylthio,methylsulphinyl, ethylsulphinyl, C₃₋₆alkylsulphinyl, methylsulphonyl,ethylsulphonyl or C₃₋₆akylsulphonyl; hydroxy; halo (eg, F, Cl or Br);R^(m)R^(n)N— where R^(m) and R^(n) are independently hydrogen orC₁₋₆alkyl (preferably C₂₋₄alkyl, more preferably methyl, most preferablyR^(m)═R^(n)=methyl); and nitro.

Where optional substitution of a ring is mentioned at various places,this most preferably refers to one, two, three or more substituentsselected from C₁₋₈alkyl (eg, C₂₋₆alkyl, and most preferably methyl);C₁₋₈alkoxy, preferably methoxy, ethoxy or C₃₋₆alkoxy; C₁₋₈alkylS(O)_(nn)wherein nn is an integer between 0 and 2, preferably methylthio,ethylthio, C₃₋₆alkylthio, methylsulphinyl, ethylsulphinyl,C₃₋₆alkylsulphinyl, methylsulphonyl, ethylsulphonyl orC₃₋₆alkylsulphonyl; halo (eg, F, Cl or Br); cyano; and NO₂.

A preferred group of compounds of the invention comprise compounds ofFormula (I) wherein:

-   R¹¹ is a group of the formula: N(⁹R¹⁰); and-   N(R⁹R¹⁰) represents an optionally-substituted 3- to 8-membered    heterocyclic ring optionally containing from 1 to 3 further    heteroatoms independently selected from O, N and S, preferably    substituted by heterocyclyl;    or a salt, pro-drug or solvate thereof.    A preferred group of compounds of the invention comprise compounds    of Formula (I) wherein:-   R¹¹ is a group of the formula: N(R⁹R¹⁰);-   R⁹ is a C₁₋₆alkyl group substituted by an optionally-substituted 3    to 8 membered heterocyclic ring containing from 1 to 4 heteroatoms    independently selected from O, N and S; and-   R¹⁰ represents hydrogen or C₁₋₆alkyl    or a salt, pro-drug or solvate thereof.

A preferred group of compounds of the invention comprises a compound ofFormula (Ib):

wherein:

-   A, B, X, R¹, R², R³, R^(3a), R⁴, R⁶, R^(6a), R⁷, R⁸, R⁹, R¹⁰, R¹¹,    R¹² and R^(12a) are as defined above;    or a salt, pro-drug or solvate thereof.

A preferred group of compounds of the invention comprises a compound ofFormula (Ic):

wherein:

-   R⁵ is selected from a IIIa, IIIb, IIIg, IIIi or IIIj:

-   and A, B, X, R¹, R³, R^(3a), R⁴, R⁶, R^(6a), R⁷, R⁸, R⁹, R¹⁰, R¹¹,    R¹², R^(12a), R¹³, and R¹⁴ are as defined above;    or a salt, pro-drug or solvate thereof.

A further preferred group of compounds of the invention comprises acompound of Formula (Id):

wherein:

-   R⁵ is selected from a IIIa, IIIb, IIIg, IIIi or IIIj:

-   and A, B, X, R¹, R², R³, R^(3a), R⁴, R⁵, R⁶, R^(6a), R⁷, R⁸, R⁹,    R¹⁰, R¹¹, R¹², R^(12a), R¹³, and R¹⁴ are as defined above;    or a salt, pro-drug or solvate thereof.

A yet further preferred group of compounds of the invention comprises acompound of Formula (Ib), (Ic) or (Id) wherein:

-   R⁵ is a group of formula IIIa:

-   NR¹³(—R¹⁴) represents an optionally substituted 7- to 8-membered    bicyclic heterocyclic ring and A, B, X, R¹, R², R³, R^(3a), R⁴, R⁶,    R^(6a), R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R^(12a) are as defined above;    or a salt, pro-drug or solvate thereof.

Particularly preferred compounds according to the present invention arewherein the compound is selected from:

2-(1,1-dimethyl-2-oxo-2-azabicyclo[2.2.1]heptan-7-ylethyl)-4-[1S-methyl-2-(N′-isopropoxycarbonyl-3-pyrid-4-yl-pyrrolidin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole;

2-(1,1-dimethyl-2-oxo-2-azabicyclo[2.2.1]heptan-7-ylethyl)-4-[2-(N′-isopropoxycarbonyl-3-pyrid-4-yl-pyrrolidin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole;

2-(2-pyrrolidin-1-yl-1,1-dimethyl-2-oxoethyl)-4-[1S-methyl-2-(N′-isopropoxycarbonyl-3-pyrid-4-yl-pyrrolidin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole;

2-(1,1-dimethyl-2-oxo-2-azabicyclo[2.2.1]heptan-7-ylethyl)-4-[1S-methyl-2-(N′-isopropoxycarbonyl-4-tetrahydropyran-4-yl-piperidin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-]pyrrole;

2-(1,1-dimethyl-2-oxo-2-azabicyclo[2.2.1]heptan-7-ylethyl)-4-[1S-methyl-2-(3-pyrid-4-yl-pyrrolidin-1-ylcarbonyl)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole;

2-(1,1-dimethyl-2-oxo-2-azabicyclo[2.2.1]heptan-7-ylethyl)-4-[1S-methyl-2-(N′-ethoxycarbonyl-3-pyrid-4-yl-pyrrolidin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole;

or a salt, pro-drug or solvate thereof.

In another embodiment of the invention particularly preferred compoundsare wherein the compound is selected from:

isopropyl(1E)({(2R)-2-[2-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxoethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrol-4-yl]propyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylidinecarbamate;

isopropyl(1E)-({2-[2-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxoethyl]-5-(3,5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrol-4-yl]ethyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylidenecarbamate;

isopropyl(1E)({(2R)-2-[2-[2-pyrrolidin-1-yl-1,1-dimethyl-2-oxoethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrol-4-yl]propyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylidinecarbamate;

methyl(1E)({(2R)-2-[2-[2-pyrrolidin-1-yl-1,1-dimethyl-2-oxoethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrol-4-yl]propyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylidinecarbamate;

isopropyl(1E)({(2R)-2-[2-[N,N-dimethylamino-1,1-dimethyl-2-oxoethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrol4-yl]propyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylidinecarbamate;

isopropyl(1E)({(2R)-2-[2-[1,1dimethyl-1-cyano-methyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrol-4-yl]propyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylidinecarbamate;

isopropyl(1E)({(2R)-2-[2-[ethoxycarbonyl-1,1-dimethyl-methyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrol-4-yl]propyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylidinecarbamate;

isopropyl(1E)({(2R)-2-[2-[aminocarbonyl-1,1-dimethyl-methyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrol-4-yl]propyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylidinecarbamate;and

N-{(2R)-2-[2-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-ylethyl)-6H-thieno[2,3-b]pyrrol-4-yl]propyl}-3-pyridin-4-ylpyrrolidine-1-carboxamide;

or a salt, pro-drug or solvate thereof.

According to a further feature of the first aspect of the inventionthere is provided a pharmaceutical formulation comprising a compound ofFormula (Ib), Formula (Ic), Formula (Id) or preferred compounds of theinvention, or salt, pro-drug or solvate thereof, and a pharmaceuticallyacceptable diluent or carrier.

According to a further feature of the first aspect of the inventionthere is provided the following uses of a compound of a compound ofFormula (Ib), Formula (Ic), Formula (Id) or preferred compounds of theinvention, or salt, pro-drug or solvate thereof:

-   (a) the use in the manufacture of a medicament for antagonising    gonadotropin releasing hormone activity;-   (b) the use in the manufacture of a medicament for administration to    a patient, for reducing the secretion of luteinizing hormone by the    pituitary gland of the patient; and-   (c) the use in the manufacture of a medicament for administration to    a patient, for therapeutically treating and/or preventing a sex    hormone related condition in the patient, preferably a sex hormone    related condition selected from prostate cancer and pre-menopausal    breast cancer.

The compounds of Formula (I) may be administered in the form of apro-drug which is broken down in the human or animal body to give acompound of the Formula (I). Examples of pro-drugs include in-vivohydrolysable esters of a compound of the Formula (I). Various forms ofpro-drugs are known in the art. For examples of such prodrugderivatives, see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and    Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et    al. (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and    Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991);-   c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);-   d) R Bundgaard, et al., Journal of Pharmaceutical Sciences, 77,285    (1988); and-   e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

An in-vivo hydrolysable ester of a compound of the Formula (I)containing a carboxy or a hydroxy group is, for example, apharmaceutically-acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid or alcohol. Suitablepharmaceutically-acceptable esters for carboxy include C₁₋₆alkoxymethylesters for example methoxymethyl, C₁₋₆alkanoyloxymethyl esters forexample pivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters.

An in-vivo hydrolysable ester of a compound of the Formula (1)containing a hydroxy group includes inorganic esters such as phosphateesters (including phosphoramidic cyclic esters) and α-acyloxyalkylethers and related compounds which as a result of the in-vivo hydrolysisof the ester breakdown to give the parent hydroxy group/s. Examples ofα-acyloxyalkyl ethers include acetoxymethoxy and2,2-dimethylpropionyloxy-methoxy. A selection of in-vivo hydrolysableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyland substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkylcarbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl.

A suitable pharmaceutically-acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitablepharmaceutically-acceptable salt of a compound of the invention which issufficiently acidic is an alkali metal salt, for example a sodium orpotassium salt, an alkaline earth metal salt, for example a calcium ormagnesium salt, an ammonium salt or a salt with an organic base whichaffords a physiologically-acceptable cation, for example a salt withmethylamine, dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

The compounds of Formula (I) can be prepared by a process comprising astep selected from (a) to (f) as follows, these processes are providedas a further feature of the invention:

-   (a) Reaction of a compound of formula XXXII as follows

-   (b) Cleavage of the cyano group of compound of formula XXXIII in the    presence of acid to produce compound of formula XXXIV

-   (c) Reaction of compound of formula XXXV as follows

-   (d) Reaction of compound of formula XXXVII as follows

-   (e) Reaction of compound of formula XXXIX as follows

-   (f) to form a compound wherein X is nitrogen and Reaction of a    compound of formula XXXXI as follows

and thereafter if necessary:

-   i) converting a compound of the Formula (I) into another compound of    the Formula (I);-   ii) removing any protecting groups;-   iii) forming a salt, pro-drug or solvate.

It will be appreciated by the processes of the present invention certainfunctional groups such as hydroxyl or amino groups in the startingreagents or intermediate compounds may need to be protected byprotecting groups. Thus, the preparation of the compounds of Formula (I)may involve, at an appropriate stage, the addition and subsequentremoval of one or more protecting groups.

The protection and de-protection of functional groups is described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ortert-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thede-protection conditions for the above protecting groups necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or alkoxycarbonyl group or an aroyl group maybe removed for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a tert-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thede-protection conditions for the above protecting groups willnecessarily vary with the choice of protecting group. Thus, for example,an acyl group such as an alkanoyl or an aroyl group may be removed, forexample, by hydrolysis with a suitable base such as an alkali metalhydroxide, for example lithium or sodium hydroxide. Alternatively anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a tert-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

EXPERIMENTAL General Reaction Schemes

In the following schemes wherein Ri, Rii and Riii represent optionalsubstituents on the phenyl ring which are optionally protected asnecessary and R represents a protecting group, group C has been depictedas substituted phenyl for illustration purposes only. Other definitionsof C are also appropriate.

Thienopyrroles, such as 3 can be synthesised by the classic Fisherthienopyrrole synthesis reaction by the condensation of a hydrazine-HCl1 and a ketone 2, bearing hydrogen atoms α to the carbonyl (Scheme a).Treatment of these reactants in a suitable solvent, such as acetic acid,ethanol, sec-butanol, toluene, in the presence of an acid, such assulphuric, hydrochloric, polyphosphoric and/or a Lewis acid, forexample, boron trifluoride, zinc chloride, magnesium bromide, atelevated temperatures (for example 100° C.), gives the desired product.R represents a protecting group, eg tert-butylcarbamate or phthalimide.

Thienopyrroles, such as represented in structure 5, can also be madeusing aldehydes 4, bearing hydrogen atoms α to the carbonyl, bycyclization using the conditions above. In this case the substituent atthe 2-position must be added later (see scheme d).

Thienopyrrole may also be synthesised utilising the Granburg reaction,wherein a hydrazine 1 is mixed with ketone 6, bearing a chlorine atom γto the carbonyl, and heated in a suitable solvent such as ethanol,sec-butanol, toluene at a temperature between 50° C. and 120° C. (Schemec).

The thienopyrrole 5 can be treated with a ‘bromine source’, such asmolecular bromide, pyridinium tribromide, pyrrolidone hydrobromide orpolymer supported reagent equivalents, in an inert solvent such aschloroform, methylene chloride at −10° C. to 25° C. to yield the 2-bromocompound 8 (Scheme d). Reaction under Suzuki conditions with apalladium(0) catalyst, a weak base such aqueous sodium carbonate orsaturated sodium hydrogen carbonate and the like, and a substituted arylboronic acid from commercial sources or prepared (as described in:Gronowitz, S.; Hornfeldt, A.-B.; Yang, Y.,-H Chem. Sci. 1986, 26,311-314), in an inert solvent such as toluene, benzene, dioxane, TBF,DMF and the like, with heating between 25° C. and 100° C., preferably80° C., for a period of 1-12 hours, to give the desired compound 3.

The thiophene 1 can be synthesised by reaction of a hydrazine under thepreferred conditions of sodium hydride in DMF at a temperature between−10° C. and −5° C., followed by reaction with di-tert-butyldicarbonatein Th under reflux.

Substituted ketones 2 can be prepared, as outlined in Scheme e startingfrom appropriate acid chlorides such as 9. Treatment of the acidchloride with N,N-dimethylhydroxylamine hydrochloride in the presence ofan amine base such as triethylamine, and a suitable solvent such asmethylene chloride at a temperature of −10° C. to 25° C., yields theamide 10. Further reaction with a substituted aryl organolithium(prepared essentially as described in Wakefield B, J.; OrganolithiumMethods Academic Press Limited, 1988, pp. 27-29 and references therein)in an inert solvent such as tetrahydrofuran, diethyl ether, benzene,toluene or mixture thereof and the like, at a temperature between −100°C. and 0° C. then quenching of the reaction mixture with a mineral acidsuch as hydrochloric acid, yields the aryl ketone 2.

Commencing with a readily available amino acid with a suitable chainlength [a] 11, the nitrogen atom can be brought in at the beginning ofthe synthesis by the route shown in Scheme f. Protection of the aminegroup of 11 with a tert-butylcarbamate group is achieved by condensationwith di-tert-butyl di-carbonate in the presence of an amine base, forexample triethylamine, in an inert solvent such as methylene chloride,chloroform, benzene, toluene, tetrahydrofuran and mixtures thereof andthe like, at a temperature of −10° C. to 25° C. Coupling of the acidproduct with N,N-dimethylhydroxylamine in the presence of a couplingreagent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC) or 1,3-dicyclohexylcarbodiimide (DCC) or the like, with or without1-hydroxybenotriazole (HOBt), and suitable amine base, such astriethylamine and the like, in an inert solvent such as methylenechloride, chloroform, dimethylformamide, or mixture thereof, at or nearroom temperature for a period of 3 to 24 hours provided thecorresponding coupled product 12. Following the same route describedabove for scheme d, the aryl group can then be installed.

Scheme g illustrates another method for the synthesis of ketone such as2 and 16, where the nitrogen group is introduced at a latter stage. Asabove a Weinreb amide 14 can be synthesised from an acid chloride.Treatment with the required amine, in an inert solvent such as THP,toluene, water and the such like can displace the group X to give 17. Asabove the aryl group can be introduced by displacement of the Weinrebamide with a suitable aryl lithium nucleophile. Alternatively thenitrogen atom can be introduced already protected as a phthalimide bydisplacement of the group x by potassium phthalimide, or similar saltthereof, by heating in an inert polar solvent such as DNF, DMSO, THF,toluene with or without the presence of a catalyst such astetrabutylammonium iodide and the such like, to yield the compound 15.Again displacement of the Weinreb amide with an organolithium speciescompletes the synthesis of a ketone suitable for cyclization under theFischer condition described above for thienopyrrole synthesis.

An alternative approach to a phthalimide protected nitrogen ketone, suchas 16, can be taken by firstly treating a lactone, with an organolithiumspecies as in the above schemes in a suitable solvent such as THF orether at a low temperature of between −100° C. and −50° C. to yield aprimary alcohol 18 (Scheme h). The hydroxyl function of 18 is replacedwith a phthalimide group by a Mitsunobu reaction with an activatingagent such as diethyldiazocarboxylate (DEAD),diisopropyldiazocarboxylate or the like with triphenylphosphine,tri-butylphosphine and the like, in an inert solvent such as benzene,toluene, tetrahydrofuran or mixtures thereof to give the desired ketone16.

If the group R¹ was not present on the starting hydrazine beforecyclization to form an thienopyrrole it may be added post cyclization byan alkylation reaction (19→3). The thienopyrrole is de-protonated by astrong base, such as sodium hydride, n-butyl lithium, lithiumdiisopropylamine, sodium hydroxide, potassium tert-butoxide in asuitable inert solvent such as THF, DMF, DMSO and the such like, and analkyl halide added and the mixture stirred at room temperature.

Depending on the route used above a thienopyrrole 20 suitable forconversion to a cyano-guandine can be formed by removal of theprotecting group, for example if a tert-butylcarbamate group was usedthen removal is accomplished using a strong acid, for exampletrifluoroacetic acid or hydrochloric acid in an inert solvent such asmethylene chloride, chloroform, THF or dioxane at a temperature between−20° C. and 25° C. A phthalimide group, for example, can be removed byhydrazine in a suitable solvent for example methanol, ethanol, methylenechloride, chloroform, THF dioxane at a temperature between −20° C. and25° C. The primary amine 20 can be converted to a cyano-guanidine 22 bythe two step process of reaction with diphenyl cyanocarbonimidate in aninert organic solvent such as iso-propyl alcohol, methylene chloride,chloroform, benzene, tetrahydrofuran and the like, at a temperaturebetween −20° C. and 50° C., followed by condensation with anappropriately substituted amine in an inert organic from the list above,with heating at a temperature between −20° C. and 100° C. (Scheme I20→21→22). Further treatment of 22 with 2 molar Hydrochloric acid inmethanol at elevated temperature yields guanidine compounds 23.

Similarly, reaction with 1,1′-bis(methylthio)-2-nitroethylene in aninert solvent such methylene chloride, chloroform, benzene,tetrahydrofuran and the like, followed by condensation with anappropriately substituted amine in an inert organic solvent from thelist above yields the nitroethyleneimidazo[1,2-α]pyridine 25 (Scheme j,20→24→25).

Again in a similar fashion the suitable thienopyrrole 20, derived fromde-protection, can be converted to a urea by either direct treatmentwith an iso-cyanate in an inert solvent such as methylene chloride,chloroform or ThF and the such like, or by a two step procedure ofreaction with triphosgene (20→27) followed by addition of an amine(27→26), bearing the required substitution to yield 26.

EXAMPLES

The invention will now be illustrated with the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

(ii) operations were carried out at room temperature, that is in therange 18-25° C. and under an atmosphere of an inert gas such as argon ornitrogen;

(iii) yields are given for illustration only and are not necessarily themaximum attainable;

(iv) the structures of the end-products of the Formula (I) wereconfirmed by nuclear (generally proton) magnetic resonance (NMR) andmass spectral techniques; proton magnetic resonance chemical shiftvalues were measured on the delta scale and peak multiplicities areshown as follows: s, singlet; d, doublet; t, triplet; mn, multiplet; br,broad; q, quartet, quin, quintet;

(v) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatography (TLC), high-performance liquidchromatography (HPLC), infra-red (IR) or NMR analysis;

(vi) chromatography was performed on silica (Merck Keiselgel: Art.9385);

(vii) isolute™ refers to silica (SiO₂) based columns with irregularparticles with an average size of 50 μm with nominal 60 Å porosity[Source: Jones Chromatography, Ltd., Glamorgan, Wales, United Kingdom].

Abbreviations brine a saturated solution of sodium chloride in distilledwater DCC 1,3-dicyclohexylcarbodiimide DEAD diethyldiazocarboxylate DMSODimethyl sulphoxide DMF dimethylformamide EDC1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBt1-hydroxybenotriazole IPA isopropyl alcohol RM reaction mixture RT roomtemperature THF tetrahydrofuranStarting Materials

The starting materials were prepared as follows:

To a suspension of NaH (54 g; 1.35 mol), and 18-crown-6 in THF (2 l)stirred at ambient temperature under argon atmosphere, 1 (100 g; 0.588mol) was added over a period of 30 minutes. After stirring overnight,the mixture was cooled at 0° C. and methyl iodide was added dropwise.The mixture was stirred at 18° C. for 3 hours, poured into a saturatedsolution of NH₄Cl and extracted with AcOEt. The organic phase wasevaporated and purified by flash chromatography eluting with petroleumether/ethyl acetate 95/5 to give 2 as an oil.

Yield: 90% ¹H NMR (CDCl₃): 1.20 (t, 3H); 1.63 (s, 6H); 4.10 (q, 2H);6.92 (m, 2H); 7.17 (m, 1H).

Nitronium tetrafluoroborate (77.9 g; 0.586 mol) was added at −55° C. toa solution of 2 (105.6 g; 0.583 mol) in DME (1.5 l). The mixture wasallowed to warm up at −10° C. over 4 hours. After extraction with ethylacetate, the organic phase was purified by flash chromatography, elutingwith petroleum ether/AcOEt 95/5 to give 3.

Yield: 86% ¹H NMR (CDCl₃): 1.23 (t, 3H); 1.65 (s, 6H); 4.14 (q, 2H);6.90 (d, 1H); 7.75 (d, 1H).

A suspension of 3 (101.7 g; 0.41 mol) and 10% Pd/C (15 g) in a mixtureof ethanol (700 ml) and ethyl acetate (300 ml) was hydrogenated underhydrogen atmosphere (5 bars) for 5 hours. After filtration of thecatalyst on celite, the residue was evaporated and redissolved in THF(900 ml); di-tert-butyl dicarbonate (100 g; 0.46 mol) was added and themixture was refluxed for 16 hours. After evaporation of the solvents,the resulting solid was taken up in petroleum ether and filtered to give5.

Yield: 68% ¹H NMR (CDCl₃): 1.20 (t, 3H); 1.48 (s, 9H); 1.58 (s, 6H);4.10 (q, 2H); 6.30 (m, 1H); 6.60 (m, 1H).

A solution of 5 (50 g; 0.16 mol) and 2N NaOH (160 ml) in ethanol (300ml) was refluxed for 1 h 30. After evaporation to dryness, the residuewas partitioned between water and ether. The aqueous layer was acidifiedwith saturated citric acid and extraction with ethyl acetate to giveafter evaporation a solid, which was triturated in pentane and filteredto give 6 as a solid.

Yield: 100% ¹H NMR (DMSOd₆): 1.48 (m, 15H); 6.30 (d, 1H); 6.59 (d, 1H).

A solution of 6 (20.1 g; 0.07 mol), EDCI (20.1 g; 0.105 mol) and DMAP(2.56 g; 0.021 mol) in dichloromethane (200 ml) was stirred under argonatmosphere for 10 minutes. Pyrrolidine (11.69 ml; 0.14 mol) was thenadded and the mixture was stirred overnight at ambient temperature.After evaporation to dryness, the residue was purified by flashchromatography eluting with AcOEt/petroleum ether 40/60 to give aftertrituration in ether/pentane 7 as a solid.

¹H NMR (CDCl₃): 1.51 and 1.57 (s, 15 H); 1.7 (m, 4H); 3.03 (br, 2H);3.50 (br, 2H); 6.35 (d, 1H); 6.48 (d, 1H); 7.26 (br, 1H).

7 (17 g; 0.05 mol) was added under argon atmosphere to a suspension ofNaH 60% (2.42 g; 0.06 mol) in dioxan (240 ml). The mixture was stirredat 100° C. for 3 hours. After cooling to 10° C., 8 (10.1 g; 0.055 mol)was added. The reaction mixture was stirred at ambient temperatureovernight. After filtration of the insoluble, the filtrate wasevaporated and purified by flash chromatography, eluting withAcOEt/petroleum ether 45/55 to give 9 as a white solid.

Yield: 89.5% ¹H NMR (CDCl₃): 1.55 and 1.57 (s, 15 H); 1.71 (s, 4H); 3.04(s, 2H); 3.50 (s, 2H); 6.53 (d, 2H); 6.70 (s, 2H).

A solution of 9 hydrochloride salt (4 g; 0.0102 mol) and 10 (6.6 g;0.0205 mol) in AcOH (20 ml) was heated at 120° C. under argon atmospherefor 3 hours. The reaction mixture was diluted with saturated NH₄Cl andextracted with AcOEt. After evaporation, the crude was purified by flashchromatography eluting with AcOEt/petroleum ether 50/50 to give 11 as afoam.

Yield: 53% MS-ESI: 540 [M+H]⁺ ¹H NMR (CDCl₃): 1.53 and 1.58 (s, 6H);1.69 (s, 4H); 2.29 (s, 6H); 3.12 (m, 4H); 3.52 (s, 2H); 3.91 (m, 2H);6.80 (m, 2H); 7.02 (s, 2H); 7.6-7.8 (m, 4H); 8.10 (s, 1H).

A solution of 11 (0.534 g; 0.99 mmol) and hydrazine (1 ml) in a mixtureof EtOH (2 ml) and CH₂Cl₂ (2 ml) was stirred under argon atmosphere atambient temperature overnight. After evaporation, the crude wasextracted in a mixture of CH₂Cl₂ and saturated NaHCO₃. The organic layerwas evaporated to give 12 as a foam.

Yield: 90% ¹H NMR (CDCl₃): 1.52 and 1.62 (s, 6H); 1.69 (s, 4H); 2.33 (s,6H); 2.80-3.2 (m, 6H); 3.52 (m, 2H); 6.74 (s, 1H); 6.93 (s, 1H); 7.05(s, 2H); 8.15 (s, 1H).

MS-ESI: 410 [M+H]⁺

Example 1.0N′-cyano-N-{2-[2-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-ylethyl)-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrol-4-yl]ethyl}-3-pyridin-4-ylpyrrolidine-1-carboximidamideExample 1.1N-{2-[2-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-ylethyl)-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrol-4-yl]ethyl}-3-pyridin-4-ylpyrrolidine-1-carboximidamide

A solution of 16 (0.160 g; 0.26 mmol) in a mixture of MeOH (8 ml) and 2NHCl (8 ml) was heated at 70° C. for 18 hours.

After neutralisation with diluted NH₄OH, the mixture was extracted withAcOEt/PrOH 10/3. The organic layer was evaporated and purified by flashchromatography eluting with a gradient 5-20% 3.5N—NH₃-MeOH/CH₂Cl₂ togive Example 1.1.

Yield: 20% MS-ESI: 583 [M+H]⁺ ¹H NMR (DMSO d6): 1.53 (s, 6H); 1.64 (mbr, 4H); 2-2.15 (m, 1H); 2.3 (s, 6H); 2.4-2.5 (m br, 1H); 3-3.10 (m,4H); 3.35-3.5 (m, 7H); 3.8 (m br, 2H); 6.83 (s, 1H); 6.91 (s, 1H); 7.09(s, 2H).

The starting material was prepared as follows:

A solution of 12 (0.527 g; 1.288 mmol) and diphenyl-N-cyanocarbonimidate(0.522 g; 2.19 mmol) in isopropanol (10 ml) was stirred at ambienttemperature under argon atmosphere for 20 hours. After evaporation todryness, the crude was purified by flash chromatography, eluting withpetroleum ether/AcOEt 80/20 to give 15.

Yield: 56%. MS-ESI: 554 [M+H]⁺

A mixture of 15 (0.38 g; 0.68 mmol) and 4-pyrrolidin-3-yl pyridine (0.38g; 2.5 mmol) in isopropanol was refluxed under argon atmosphere for 20hours. After evaporation to dryness, the mixture was purified by flashchromatography, eluting with a gradient 4-8% MeOH/CH₂Cl₂ to give Example1.0.

Yield: 66%. MS-ESI: 606 [M−H]⁻ ¹H NMR (CDCl₃): 1.62 (s, 6H); 1.6-1.7 (mbr, 4H); 1.85-2 (m, 1H); 2.2-2.35 (m, 1H); 2.3 (s, 6H); 3.05-3.8 (m, 13H); 4.4 (t, 1H NH); 6.73 (s, 1H); 6.88 (s, 1H); 7.04 (d, 2H); 7.05 (s,2H); 8.47 (s, 1H 1NH); 8.52 (d, 2H).

Examples 1.2-1.6

Following a procedure similar to that described in example 1, thefollowing compounds were prepared.

Example MS-ESI 1.2

648 [M + H]⁺ 1.3

623 [M + H]⁺ 1.4

648 [M + H]⁺ 1.5

634 [M + H]⁺ 1.6

609 [M + H]⁺

Example 22-(1,1-dimethyl-2-oxo-2-azabicyclo[2.2.1]heptan-7-ylethyl)-4-[1S-methyl-2-(N′-isopropoxycarbonyl-3-pyrid-4-yl-pyrrolidin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole

To a solution of 19 (0.325 g; 0.54 mmol) in CH₂Cl₂ (10 ml) at 0° C. wasadded under argon atmosphere 4-pyrrodidin-3-yl pyridine (0.122 g; 0.82mmol), EDC (0.158 g; 0.82 mmol) and DIEA (0.142 ml; 0.82 mmol). Themixture was stirred at 0° C. for 15 minutes allowed to warm up andstirred for 24 hours at ambient temperature. The reaction mixture wasextracted with CH₂Cl₂. The organic layer was evaporated and the crudematerial was purified by flash chromatography eluting with AcOEt andMeOH—NH₃ 97.5/2.5 95/5 to give Example 2 as a solid.

Yield: 55%. ¹H NMR (CDCl₃): 1.2 (m, 6H); 1.2-1.3 (m, 4H); 1.4 (m, 3H);1.5-1.68 (m, 4H); 1.55 (s, 6H); 1.7-1.9 (m, 1H); 2.1-2.2 (m, 1H); 2.28(m, 6H); 3.02-3.5 (m, 7H); 3.6 (m, 1H); 4.05 (s broad, 1H); 4.7 (sbroad, 1H); 4.82 (m, 1H); 6.72 (s, 1H); 6.9 (m, 1H); 7.0 (s, 1H); 7.05(d, 2H); 8.20 (s, 1H); 8.50 (d, 2H) MS-ESI: [M+H]⁺ 709

The starting material was prepared as follows:

To a solution of 21 (0.098 g; 0.66 mmol) in CH₂Cl₂ (1.5 ml) was added at0° C., a solution of 20 (0.3 g; 0.66 mmol) in CH₂Cl₂ (1.5 ml). Themixture was stirred at ambient temperature for 90 minutes and extracted.The organic layer was evaporated and purified by flash chromatography,eluting with CH₂Cl₂/AcOEt 50/50 to give 19.

Yield: 90% ¹H NMR (CDCl₃): 1.2 (m, 6H); 1.2-1.35 (m, 4H); 1.38 (d, 3H);1.50-1.80 (m, 4H); 1.55 (s, 6H); 2.35 (s, 6H); 3.45 (m, 1H); 1.78 (m,1H); 4.00 (m, 1H); 4.10 (s broad 1H); 4.75 (s broad, 1H); 4.87 (m, 1H);6.80 (s, 1H); 6.96 (s, 1H); 7.07 (s, 2H); 7.72 (s, 1H); 8.10 (s, 1H);9.54 (s, 1H). MS-ESI: [M+H]⁺ 595

Preparation of 20 is described in Example 8.

Examples 2.1-2.7

Following a procedure similar to that described in example 3, thefollowing examples were prepared.

Example MS-ESI 2.1

695 [M + H]⁺ 2.2

683 [M + H]⁺ 2.3

655 [M + H]⁺ 2.4

657 [M + H]⁺ 2.5

611 [M + H]⁺ 2.6

658 [M + H]⁺ 2.7

629 [M + H]⁺ 2.8

724 [M + H]⁺ 2.9

709 [M + H]⁺ 2.10

724 [M + H]⁺ 2.11

724 M + H]⁺ 2.12

730 M + H]⁺ 2.13

746 M + H]⁺

Example 32-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-ylethyl)-4-[1S-methyl-2-(3-{pyridin-4-yl}pyrrolidin-1-yl)carbonylamino-ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole

4-nitrophenyl chloroformate (0.127 g; 0.63 mmol) was added under argonatmosphere, at 0° C. to a solution of 22 (0.254 g; 0.60 mmol) andtriethylamine −0.088 ml; 0.63 mmol) in methylene chloride (4 ml). Themixture was stirred at 0° C. for 30 minutes and at ambient temperaturefor 1 hour. 4-pyrrolidin-3-yl pyridine (0.098 g; 0.72 mmol) in solutionin methylene chloride (0.5 ml) was added. The mixture was stifled for 2hours and purified by flash chromatography eluting with a gradient 2-6%MeOH/CH₂Cl₂ to give Example 3 as a solid.

Yield: 80% MS-ESI: 598 [M+M]⁺ ¹HNMR (CDCl₃): 1.37 (d, 3H); 1.6 (s, 6H);1.6-1.75 (m, 4H); 1.75-2 (m, 1H); 2.2-2.3 'm, 1H); 2.29 (s, 6H); 3-3.4(m, 8H); 3.45-3.8 (m, 4H); 4.12 (m, 1H, NH); 6.77 (s, 1H); 6.91 (m, 1H);7-7.1 (m, 4H); 8.28 (s, 1H, NH); 8.48 (s, br, 2H).

22 was prepared following a procedure similar to that described inexample 1 for compound 12.

Examples 3.1-3.5

Following a procedure similar to that described in example 4, thefollowing examples were prepared.

Example MS-ESI 3.1

572 [M + H]⁺ 3.2

574 [M + H]⁺ 3.3

607 [M + H]⁺ 3.4

520 [M + H]⁺ 3.5

624 [M + H]⁺ 3.6

638 [M + H]⁺

Example 42-(1,1-dimethyl-2-oxo-2-azabicyclo[2.2.1]heptan-7-ylethyl)-4-[1S-methyl-2-(N′-ethoxycarbonyl-3-pyrid-4-yl-pyrrolidin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole

Example 4 was prepared following a procedure similar to that describedin example 2.

Yield: 63% ¹H NMR (CDCl₃) 1.25 (multiplet, 3H); 1.25-1.38 (m, 6H); 1.43(multiplet, 3H); 1.62 (s, 6H); 1.45-2.20 (multiplets, 5H); 2.32 (s, 6H);3.00-3.55 (multiplets, 7H); 3.65 (multiplet, 1H); 4.1 (sb, 1H); 4.07(multiplet, 2H); 4.80 (sb, 1H); 6.75 (s, 1H); 6.93 (d, 1H); 7.02 (m,3H);7.07 (d, 1H); 8.27 (s, 1H); 8.51 (multiplet, 2H). MS-ESI: 695 [M+H]⁺

The starting material was prepared as follows:

To a solution of 24 (0.350 g; 2.66 mmol) in CH₂Cl₂ (8 ml) was added at0° C., a solution of 20 (1.5 g; 2.66 mmol) and DIEA (0.463 ml; 2.66mmol) in CH₂Cl₂ (8 ml). The mixture was stirred at ambient temperaturefor 2 hours. After evaporation, the residue was purified by flashchromatography, eluting successively with CH₂Cl₂ and CH₂Cl₂/AcOEt 585/15to give 23.

Yield: 100% ¹H NMR (CDCl₃) 1.209 (t, 3H); 1.25-1.55 (m, 4H); 1.45-1.80(m, 4H); 1.627 (d, 3H); 1.591 (s, 6H); 2.355 (s, 6H); 3.473 (multiplet,1H); 3.770 (multiplet, 1H); 4.05 (quintuplet, 1H); 4.1 (sb, 1H); 4.130(quadruplet, 2H); 4.85 (sb, 1H); 6.806 (s, 1H); 6.968 (s, 1H); 7.069 (s,2H); 7.799 (s, 1H) 8.129 (s, 1H); 9.55 (s, 1H).

Example 52-(1,1-dimethyl-2-oxo-2-azabicyclo[2.2.1]heptan-7-ylethyl)-4-[1S-methyl-2-(N′-isoethoxycarbonyl-4-{morpholinocarbonyl}piperazin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole

To a mixture of 24 (0.095 g; 0.15 mmol) and K₂CO₃ (0.23 g: 0.165 mmol)in CH₃CN (3 ml) was added under argon atmosphere, 25 (0.025 g; 0.165mmol). The mixture was stirred at ambient temperature for 20 hours.After evaporation to dryness, the residue was purified by flashchromatography, eluting successively with CH₂Cl₂, CH₂Cl₂/AcOEt 50/50 andNH3/AcOEt 2/98 to give after trituration in ether:pentane Example 5 as asolid.

Yield: 72%. ¹H RMN (CDCl₃)1.270 (t, 3H); 1.20-1.35 (m, 4H); 1.392 (d,3H); 1.45-1.75 (m, 4H); 1.604 (s, 6H); 2.352 (s, 6H); 3.132-3.32(multiplets, 15H); 3.67 (multiplet, 4H); 4.025 (quadruplet, 2H); 4.05(sb, 1H); 4.75 (sb, 1H ); 6.736 (s, 1H); 6.968 (s, 1H); 7.020(s, 2H);7.965 (s, 1H); 8.217 (s, 1H). MS-ESI: 746 [M+H]⁺

The starting material was prepared as follows

To a solution of 23 (0.156 g; 0.27 mmol) in CH₂Cl₂ (6 ml) at 0° C. wasadded under argon atmosphere 27 (0.076 g; 0.405 mmol), EDC (0.078 g;0.405 mmol) and DIEA (0.07 ml; 0.405 mmol). The mixture was stirred at0° C. for 15 minutes allowed to warm up and stirred for 24 hours atambient temperature. The reaction mixture was extracted with CH₂Cl₂. Theorganic layer was evaporated and the crude material was purified byflash chromatography eluting successively with methylene chloride,methylene chloride/AcOEt 50/50 and 3.5 N NH₃ MeOH/AcOEt 5/95 to give 26as a solid.

Yield: 58% ¹H NMR (CDCl₃) 1.235 (t, 3H); 1.20-1.35 (m, 4H); 1.396 (d,3H); 1.450 (s, 9H); 1.55-1.75 (m, 4H); 1.598 (s, 6H); 2.352 (s, 6H);3.131-3.379 (multiplets, 11H); 4.025 (quadruplet, 2H); 4.05 (sb, 1H);4.75 (sb, 1H); 6.744 (s, 1H); 6.970 (s, 1H); 7.017 (s, 2H); 7.92 (s,1H); 8.188 (s, 1H).

26 (0.06 g; 0.82 mmol) was dissolved in methylene chloride (0.6 ml) andtreated with a solution made of 12N HCl/dioxan 5/25 (1 ml). The mixturestirred under argon atmosphere overnight. After evaporation to dryness,the residue was neutralised and extracted with AcOEt. The organic layerwas separated, dried and evaporated to dryness. The residue wastriturated with methylene chloride/ether to give 27 triturated in amixture of MeOH, methylene chloride and ether to give 24 as solid.

Yield: 88% ¹H RMN (CDCl₃) 1.235 (t, 3H); 1.20-1.35 (m, 4H); 1.33 (d,3H); 1.45-1.75 (m, 4H); 1.62 (s, 6H); 2.35 (s, 6H); 2.85 (multiplet,4H); 3.26-3.38 (multiplets, 7H); 4.025 (quadruplet, 2H); 4.05 (sb, 1H);4.75 (sb, 1H); 6.74 (s, 1H); 6.96 (s, 1H); 7.02 (s, 2H); 8.01 (s, 1H);8.41 (s, 1H); +1 NH.

Example 62-(1,1-dimethyl-2-oxo-2-azabicyclo[2.2.1]heptan-7-ylethyl)-4-[1S-methyl-2-(N′-aminocarbonyl-3-pyrid-4-yl-pyrrolin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole

To a stirred solution of 28 (0.39 g; 0.603 mmol) in THF (5 ml) at roomtemperature, was added a 18% (v/v) aqueous solution of HCl. Theresulting yellow solution was heated at 80° C. for 4 hours after whichHPLC showed no remaining starting material. The reaction mixture wasallowed to cool down to room temperature and concentrated on a rotaryevaporator. A solution of saturated aqueous brine (5 ml) and saturatedaqueous NaHCO₃ (5 ml) were added and the resulting oil was extractedwith DCM (100 ml). The organic layer was separated, washed with brine(10 ml), dried over magnesium sulfate and concentrated to afford anorange gum. The gum was dissolved in DCM (1 ml) and purified by flashchromatography on silica gel eluting with DCM-MeOH (95:5) to afford theExample 6 (0.067 g).

Yield: 16.8%. ¹H NMR (CDCl₃) (δ ppm) 1.22-1.75 (m, 15H); 1.88-1.94 (m,1H); 2.15-2.47 (m, 9H); 3.23-3.73(m, 8H); 4.07 (sb, 1H); 4.76 (sb, 1H);6.74 (m, 1H); 6.97 (m, 1H); 6.98-7.11 (m, 4H); 8.56 (m, 2H). MS-ESI: 666[M+H]⁺

The intermediate 24 was prepared using similar chemistry than that usedfor the preparation of Example 1.0.

Example 72-(1,1-dimethyl-2-oxo-2-azabicyclo[2.2.1]heptan-7-ylethyl)-4-[1S-methyl-2-(N′-methylcarbonyl-3-pyrid-4-yl-pyrrolidin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole

To a stirred solution of 29 (0.193 g; 0.351 mmol), DIPEA (0.068 g; 0.527mmol) and 4-pyrrolidin-3-yl pyridine (0.057 g; 0.386 mmol) in DMF (1 ml)at room temperature, was added solid EDCI (0.074 g; 0.386 mmol). Thereaction mixture was heated at 80° C. for 16 hours after which HPLCshowed no remaining starting material. The reaction mixture was cooledto room temperature, triturated with water (5 ml) and the resultingsolid was collected by filtration, dissolved in DCM (2 ml) and purifiedby flash chromatography on silica gel eluting with DCM-MeOH (97:3) toafford Example 7 (0.03 g).

Yield: 12%. ¹H NMR (CDCl₃) (δ ppm) 1.22-1.37 (m, 7H); 1.43 (m, 2H);1.52-1.74(m,8H); 1.88-1.94 (m, 1H); 2.06 (m, 3H); 2.19-2.42 (m, 8H);3.23-3.41 (m, 5H); 3.57 (m, 2H); 4.07 (sb, 1H); 4.73 (sb, 1H); 6.77 (s,1H); 6.96 (m, 1H); 7.04-7.11 (m, 4H); 8.27 (s, 1H); 8.53 (m, 2H).MS-ESI: 665 [M+H]⁺

The intermediate 29 was prepared using similar chemistry than thatdescribed for the preparation of intermediate 19.

Example 82-(1,1-dimethyl-2-oxo-2-azabicyclo[2.2.1]heptan-7-ylethyl)-4-[1S-methyl-2-(N′-hydroxy-3-pyrid-4-yl-pyrrolidin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole

To a stirred solution of 30 (0.152 g; 0.173 mmol) in diethyl ether (5ml) at 0° C., were added MeOH (1 ml) and a 4.0M solution of HCl in1,4-dioxane (5 ml). The solvent was evaporated to dryness and theresidue was suspended in toluene and evaporated to dryness again andfurther dried under high vacuum. The resulting white foam was trituratedwith diethyl ether (20 ml) and the resulting white solid collected byfiltration, washed with diethyl ether (2×5 ml) and dried to a constantweight to afford Example 8.HCl (0.106 g) as a white solid.

Yield: 85.4%. ¹H NMR (DMSO-d₆) (δ ppm) 1.32 (m, 7H); 1.52 (m, 10H);1.84-2.04 (m, 4H); 2.25-2.32 (m, 6H); 3.23-3.72 (m, 8H); 4.03 (sb, 1H);4.45 (sb, 1H); 6.84-7.93(m, 2H); 7.05 (m, 2H); 7.35 (m, 1H); 7.53 (m,1H); 7.66 (m, 1H); 7.74 (m, 1H); 8.79 (m, 2H); 10.11-10.19 (m, 1H);10.55-10.63 (m, 1H); 11.38 (m, 1H). MS-ESI: 639 [M+]⁺

The intermediate 30 was prepared as follows:

The intermediate 35 was prepared using similar chemistry to that usedfor the preparation of 9.

To a stirred suspension of 35 (17 g; 45.0 mmol) and 34 (22.5 g; 67.0mmol) in 2-butanol (50 ml) was added a 4M solution of HCl in 1,4-dioxane(22.5 ml; 90.0 mmol). The resulting thick suspension was heated at 90°C. for 1 hour after which HPLC showed no remaining starting material.The resulting dark brown solution was evaporated to dryness on a rotaryevaporator and the residue was dissolved in DCM and purified by flashchromatography on silica gel eluting with ethyl acetate-petroleum ether40/60 (10:90 to 50/50) to afford 33 (16 g) as a white solid.

Yield: 54% ¹H NMR (CDCl₃) (δ ppm) 1.26-1.40 (m, 7H); 1.57 (s, 6H);1.63-1.83 (m, 4H); 2.32 (s, 6H); 3.66 (m, 1H); 3.87 (m, 2H); 4.20 (sb,1H); 4.75 (sb, 1H); 6.86 (s, 1H); 6.92(s, 1H); 6.98 (s, 2H); 7.67 (m,2H); 7.74 (m, 2H); 8.03 (s, 1H). MS-ESI: 580 [M+H]⁺

To a stirred suspension of 33 (14 g; 24.0 mmol) in ethanol (300 ml) atroom temperature, was added neat hydrazine monohydrate (12 ml; 240mmol). The reaction mixture was stirred at room temperature for 16 hoursafter which HPLC showed no remaining starting material. The resultingprecipitate was collected by filtration, washed with ethanol (2×20 ml)and the filtrate was evaporated to dryness on a rotary evaporator anddried to a constant weight under high vacuum to afford 20 (10.9 g) as ayellow foam which was used without further purification.

Yield: 100% MS-ESI: 450 [M+H]⁺ ¹H NMR (CDCl₃) (δ ppm) 1.27-1.36 (m, 7H);1.43-1.53 (m, 10H); 2.34 (s, 6H); 3.06 (m, 1H); 3.23 (m, 1H); 3.28 (m,1H); 4.10 (sb, 1H); 4.50 (sb, 1H); 6.87 (s, 1H); 6.96 (s, 1H); 7.07 (s,2H).

To a stirred solution of 1,1′-thiocarbonyldiimidazole (0.08 g; 0.45mmol) in MeCN (5 ml) at 0° C., was added a solution of 20 (0.20 g; 0.45mmol) and DIPEA (0.058 g; 0.45 mmol) in DCM (5 ml). The resultingsolution was stirred at room temperature for 1 hour after which HPLCshowed no remaining starting material. A 50% (v/v) solution ofhydroxylamine in water (0.297 g; 9.00 mmol) was added and the resultingsolution was stirred at room temperature for 2 hours after which HPLCshowed no remaining starting material. The reaction mixture wasevaporated to dryness and the residue was purified by flashchromatography on silica gel eluting with DCM-MeCN (70:30) to afford 32(0.160 g) as a beige foam.

Yield: 67.8%. MS-ESI: 525 [M+H]⁺

To a stirred solution of 32 (0.20 g; 0.38 mmol) and triethylamine (0.058g; 0.57 mmol) in DCM (10 ml) at room temperature, was addedtriphenylmethyl chloride (0.117 g; 0.42 mmol). The resulting solutionwas stirred at room temperature for 1 hour after which HPLC showed noremaining starting material. The solvent was evaporated on a rotaryevaporator and the residue was purified by flash chromatography onsilica gel eluting with DCM-MeCN (80:20) to afford 31 (0.198 g) as awhite foam.

Yield: 68%. MS-ESI: 767 [M+H]⁺

To a stirred solution of 31 (0.198 g; 0.26 mmol), DIPEA (0.050 g; 0.39mmol) and 4-pyrrolidin-3-yl pyridine (0.039 g; 0.26 mmol) in DCM (2 ml)at room temperature, was added solid EDCI (0.075 g; 0.39 mmol). Thereaction mixture was stirred at room temperature for 16 hours afterwhich HPLC showed no remaining starting material. The reaction mixturewas purified by flash chromatography on silica gel eluting with DCM-MeCN(90:10) to afford 30 (0.192 g) as a pale yellow foam.

Yield: 83.8%. MS-ESI: 881 [M+H]⁺

Example 92-(1,1-dimethyl-2-oxo-2-azabicyclo[2.2.1]heptan-7-ylethyl)-4-[1S-methyl-2-(N′-methoxycarbonyl-3-pyrid-4-yl-pyrrolidin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole

Example 9 was prepared using similar chemistry to that described forexample 8.

Yield: 52%. ¹H NMR (CDCl₃) (δ ppm) 1.22-1.43 (m, 7H); 1.52-1.73 (m,10H); 1.79-1.92 (m, 2H); 2.25 (m, 2H); 2.36 (s, 6H); 3.23-3.28 (m, 6H);3.46 (m, 3H); 4.03 (sb, 1H); 4.75 (sb, 1H); 6.74 (s, 1H); 6.96 (s, 1H);7.07 (s, 2H); 7.12 (d, 1H); 7.16 (d, 1H); 8.15 (s, 1H); 8.53 (m, 2H).MS-ESI: 653 [M+H]⁺

Therapeutic Uses

Compounds of Formula (I) are provided as medicaments for antagonisinggonadotropin releasing hormone (GnRH) activity in a patient, eg, in menand/or women. To this end, a compound of Formula (I) can be provided aspart of a pharmaceutical formulation which also includes apharmaceutically acceptable diluent or carrier (eg, water). Theformulation may be in the form of tablets, capsules, granules, powders,syrups, emulsions (eg, lipid emulsions), suppositories, ointments,creams, drops, suspensions (eg, aqueous or oily suspensions) orsolutions (eg, aqueous or oily solutions). If desired, the formulationmay include one or more additional substances independently selectedfrom stabilising agents, wetting agents, emulsifying agents, buffers,lactose, sialic acid, magnesium stearate, terra alba, sucrose, cornstarch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butterand ethylene glycol.

The compound is preferably orally administered to a patient, but otherroutes of administration are possible, such as parenteral or rectaladministration. For intravenous, subcutaneous or intramuscularadministration, the patient may receive a daily dose of 0.1 mgkg⁻¹ to 30mgkg⁻¹ (preferably, 5 mgkg⁻¹ to 20 mgkg⁻¹) of the compound, the compoundbeing administered 1 to 4 times per day. The intravenous, subcutaneousand intramuscular dose may be given by means of a bolus injection.Alternatively, the intravenous dose may be given by continuous infusionover a period of time. Alternatively, the patient may receive a dailyoral dose which is approximately equivalent to the daily parenteraldose, the composition being administered 1 to 4 times per day. Asuitable pharmaceutical formulation is one suitable for oraladministration in unit dosage form, for example as a tablet or capsule,which contains between 10 mg and 1 g (preferably, 100 mg and 1 g) of thecompound of the invention.

Buffers, pharmaceutically acceptable co-solvents (eg, polyethyleneglycol, propylene glycol, glycerol or EtOH) or complexing agents such ashydroxy-propyl β cyclodextrin may be used to aid formulation.

One aspect of the invention relates to the use of compounds according tothe invention for reducing the secretion of LH and/or FSH by thepituitary gland of a patient. In this respect, the reduction may be byway of a reduction in biosynthesis of the LH and FSH and/or a reductionin the release of LH and FSH by the pituitary gland. Thus, compoundsaccording to the invention can be used for therapeutically treatingand/or preventing a sex hormone related condition in the patient. By“preventing” we mean reducing the patient's risk of contracting thecondition. By “treating” we mean eradicating the condition or reducingits severity in the patient. Examples of sex hormone related conditionsare: a sex hormone dependent cancer, benign prostatic hypertrophy, myomaof the uterus, endometriosis, polycystic ovarian disease, uterinefibroids, prostatauxe, myoma uteri, hirsutism and precocious puberty.Examples of sex hormone dependent cancers are: prostatic cancer, uterinecancer, breast cancer and pituitary gonadotrophe adenoma.

The compounds of the invention may be used in combination with otherdrugs and therapies used to treat/prevent sex-hormone relatedconditions.

If formulated as a fixed dose such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically-active agent within its approved dosagerange. Sequential use is contemplated when a combination formulation isinappropriate.

In the field of medical oncology examples of such combinations includecombinations with the following categories of therapeutic agent:

i) anti-angiogenic agents (for example linomide, inhibitors of integrinαvβ3 function, angiostatin, endostatin, razoxin, thalidomide) andincluding vascular endothelial growth factor (VEGF) receptor tyrosinekinase inhibitors (RTKIs) (for example those described in internationalpatent applications publication nos. WO-97/22596, WO-97/30035,WO-97/32856 and WO-98/13354, the entire disclosure of which documents isincorporated herein by reference);

ii) cytostatic agents such as anti-oestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene, iodoxyfene), progestogens (forexample megestrol acetate), aromatase inhibitors (for exampleanastrozole, letrozole, vorazole, exemestane), anti-progestogens,anti-androgens (for example flutamide, nilutamide, bicalutamide,cyproterone acetate), inhibitors of testosterone 5α-dihydroreductase(for example finasteride), anti-invasion agents (for examplemetalloproteinase inhibitors like marimastat and inhibitors of urokinaseplasminogen activator receptor function) and inhibitors of growth factorfunction, (such growth factors include for example epidermal growthfactor (EGF), platelet derived growth factor and hepatocyte growthfactor such inhibitors include growth factor antibodies, growth factorreceptor antibodies, tyrosine kinase inhibitors and serine/threoninekinase inhibitors);

iii) biological response modifiers (for example interferon);

iv) antibodies (for example edrecolomab); and

v) anti-proliferative/anti-neoplastic drugs and combinations thereof, asused in medical oncology, such as anti-metabolites (for exampleanti-folates like methotrexate, fluoropyrimidines like 5-fluorouracil,purine and adenosine analogues, cytosine arabinoside); anti-tumourantibiotics (for example anthracyclines like doxorubicin, daunomycin,epirubicin and idarubicin, mitomycin-C, dactinomycin, mithramycin);platinum derivatives (for example cisplatin, carboplatin); alkylatingagents (for example nitrogen mustard, melphalan, chlorambucil,busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa);anti-mitotic agents (for example vinca alkaloids like vincristine andtaxoids like taxol, taxotere); enzymes (for example asparaginase);thymidylate synthase inhibitors (for example raltitrexed); topoisomeraseinhibitors (for example epipodophyllotoxins like etoposide andteniposide, amsacrine, topotecan, irinotecan).

The compounds of the invention may also be used in combination withsurgery or radiotherapy.

Assays

The ability of compounds according to the invention to act asantagonists of GnRH can be determined using the following in vitroassays.

Binding Assay Using Rat Pituitary GnRH Receptor

The assay is performed as follows:

-   1. Incubate crude plasma membranes prepared from rat pituitary    tissues in a Tris.HCl buffer (pH. 7.5, 50 mM) containing bovine    serum albumin (0.1%), [I-125]D-t-Bu-Ser6-Pro9-ethyl amide-GnRH, and    the test compound. Incubation is at 4° C. for 90 minutes to 2 hours.-   2. Rapidly filter and repeatedly wash through a glass fibre filter.-   3. Determine the radioactivity of membrane bound radio-ligands using    a gamma counter.

From this data, the IC₅₀ of the test compound can be determined as theconcentration of the compound required to inhibit radio-ligand bindingto GnRH receptors by 50%. Compounds according to the present inventionhave activity at a concentration from 1 nM to 5 μM.

Binding Assay Using Human GnRH Receptor

Crude membranes prepared from CHO cells expressing human GnRH receptorsare sources for the GnRH receptor. The binding activity of compoundsaccording to the invention can be determined as an IC₅₀ which is thecompound concentration required to inhibit the specific binding of[¹²⁵I]buserelin to GnRH receptors by 50%. [¹²⁵I]Buserelin (a peptideGnRH analogue) is used here as a radiolabelled ligand of the receptor.

Assay to Determine Inhibition of LH Release

The LH release assay can be used to demonstrate antagonist activity ofcompounds, as demonstrated by a reduction in GnRH-induced LH release.

Preparation of Pituitary Glands

Pituitary glands obtained from rats are prepared as follows. Suitablerats are Wistar male rats (150-200 g) which have been maintained at aconstant temperature (eg, 25° C.) on a 12 hour light/12 hour dark cycle.The rats are sacrificed by decapitation before the pituitary glands areaseptically removed to tube containing Hank's Balanced Salt Solution(HBSS). The glands are further processed by:—

-   1. Centrifugation at 250×g for 5 minutes;-   2. Aspiration of the HBSS solution;-   3. Transfer of the glands to a petri dish before mincing with a    scalpel;-   4. Transfer of the minced tissue to a centrifuge tube by suspending    the tissue three successive times in 10 ml aliquots of HBSS    containing 0.2% collagenase and 0.2% hyaluronidase;-   5. Cell dispersion by gentle stirring of the tissue suspension while    the tube is kept in a water bath at 37° C.;-   6. Aspiration 20 to 30 times using a pipette, undigested pituitary    fragments being allowed to settle for 3 to 5 minutes;-   7. Aspiration of the suspended cells followed by centrifugation at    1200×g for 5 minutes;-   8. Re-suspension of the cells in culture medium of DMEM containing    0.37% NaHCO₃, 10% horse serum, 2.5% foetal bovine serum, 1% non    essential amino acids, 1% glutamine and 0.1% gentamycin;-   9. Treatment of the undigested pituitary fragments 3 times with 30    ml aliquots of the collagenase and hyaluronidase;-   10. Pooling of the cell suspensions and dilution to a concentration    of 3×10⁵ cells/ml;-   11. Placing of 1.0 ml of this suspension in each of a 24 well tray,    with the cells being maintained in a humidified 5% CO₂/95% air    atmosphere at 37° C. for 3 to 4 days    Testing of Compounds

The test compound is dissolved in DMSO to a final concentration of 0.5%in the incubation medium.

1.5 hours prior to the assay, the cells are washed three times with DMEMcontaining 0.37% NaHCO₃, 10% horse serum, 2.5% foetal bovine serum, 1%non essential amino acids (100×), 1% glutamine (100×), 1%penicillin/streptomycin (10,000 units of each per ml) and 25 mM HEPES atpH 7.4. Immediately prior to the assay, the cells are again washed twicein this medium.

Following this, lml of fresh medium containing the test compound and 2nM GnRH is added to two wells. For other test compounds (where it isdesired to test more than one compound), these are added to otherrespective duplicate wells. Incubation is then carried out at 37° C. forthree hours.

Following incubation, each well is analysed by removing the medium fromthe well and centrifuging the medium at 2000×g for 15 minutes to removeany cellular material. The supernatant is removed and assayed for LHcontent using a double antibody radio-immuno assay. Comparison with asuitable control (no test compound) is used to determine whether thetest compound reduces LH release. Compounds according to the presentinvention have activity at a concentration from 1 nM to 5 μM.

1. A compound of Formula (I),

wherein A represents a direct bond or optionally substitutedC₁₋₅alkylene; B is a group of Formula (II):

 wherein at position (a) Formula (II) is attached to the nitrogen atomand the group X is attached to R⁸; R¹ represents hydrogen; optionallysubstituted C₁₋₈alkyl; or (CH₂)_(b)—R^(a), wherein R^(a) representsC₃₋₈cycloalkyl and b is zero or an integer from 1 to 6; R² represents anoptionally substituted mono- or bi-cyclic aromatic ring structurewherein the optional substituents are selected from cyano, NR³R^(3a),optionally substituted C₁₋₈alkyl, optionally substituted C₁₋₈alkoxy orhalo; R³ and R^(3a) are independently selected from hydrogen; optionallysubstituted C₁₋₈alkyl and optionally substituted aryl; R⁴ is hydrogen;R⁵ is selected from an optionally substituted 3- to 8-memberedheterocyclic ring containing from 1 to 4 heteroatoms independentlyselected from O, N and S; or a group of formula III-a; III-b; III-c;III-d; III-e; III-f, III-g, III-h, III-i, III-j, III-k or III-l;

 wherein het represents an optionally substituted 3- to 8-memberedheterocyclic ring containing from 1 to 4 heteroatoms independentlyselected from O, N and S; R⁶ and R^(6a), are independently selected fromhydrogen and optionally substituted C₁₋₈alkyl; or R⁶ and R^(6a) togetherrepresent carbonyl; R⁷ represents hydrogen or optionally substitutedC₁₋₈alkyl; or

 together form an optionally substituted 3- to 8-membered heterocyclicring containing from 1 to 3 further heteroatoms independently selectedfrom O, N and S, and R^(6a) represents hydrogen and optionallysubstituted C₁₋₈alkyl; X and R⁸ are selected from: (i) X represents Nand R⁸ is selected from: cyano, hydrogen, hydroxy, —O—R^(b),—C(O)—R^(b), —NR^(b)R^(c)—C(O)O—R^(b), —CONR^(b)R^(c) or NH—C(O)—R^(b),where R^(b) and R^(c) are independently selected from hydrogen andC₁₋₄alkyl optionally substituted with hydroxy, amino, N—C₁₋₄alkylamino,N,N-di-C₁₋₄alkylamino, HO—C₂₋₄alkyl-NH— or HO—C₂₋₄alkyl-N(C₁₋₄alkyl)-;(ii) X represents CH and R⁸ represents NO₂; and (iii) ═X—R⁸ represents═O; R¹¹ is a group of the formula: N(R⁹R¹⁰) wherein R⁹ representshydrogen, optionally substituted aryl, an optionally substituted 3- to10 membered heterocyclic ring or optionally-substituted C₁₋₈alkyl andR¹⁰ represents hydrogen or optionally substituted C₁₋₈alkyl; or thestructure N(R⁹R¹⁰) represents an optionally-substituted 3- to 10membered heterocyclic ring optionally containing from 1 to 3 furtherheteroatoms independently selected from O, N and S; R¹² and R^(12a) areindependently selected from hydrogen or optionally substitutedC₁₋₈alkyl; or R¹² and R^(12a) together with the carbon to which they areattached form an optionally substituted 3 to 7-membered cycloalkyl ring;R¹³ and R¹⁴ are selected from: (i) R¹³ is selected from hydrogen;optionally substituted C₁₋₈alkyl; optionally substituted aryl;—R^(d)—Ar, where R^(d) represents C₁₋₈alkylene and Ar representsoptionally substituted aryl; and optionally substituted 3- to 8-memberedheterocyclic ring optionally containing from 1 to 3 further heteroatomsindependently selected from O, N and S; and R¹⁴ is selected fromhydrogen; optionally substituted C₁₋₈alkyl and optionally substitutedaryl; (ii) where R⁵ represents a group of formula III-a, III-b, III-i orIII-k, then the group NR¹³(—R¹⁴) represents an optionally substituted 3-to 8-membered heterocyclic ring optionally containing from 1 to 3further heteroatoms independently selected from O, N and S; or (iii)where R⁵ represents structure III-e, then the group

 represents an optionally substituted 3- to 8-membered heterocyclic ringoptionally containing from 1 to 4 heteroatoms independently selectedfrom O, N and S; R¹⁷ is selected from: hydrogen and C₁₋₄alkyl; or asalt, pro-drug or solvate thereof.
 2. A compound according to claim 1wherein R⁹ represents hydrogen, optionally substituted aryl, anoptionally substituted 3- to 10 membered heterocyclic ring oroptionally-substituted C₁₋₈alkyl and R¹⁰ represents hydrogen oroptionally substituted C₁₋₈alkyl wherein the optional substituents onaryl, the heterocyclic ring and C₁₋₈alkyl are selected from: hydroxy,amino, nitro, cyano, optionally-substituted aryl, optionally substituted3- to 8-membered heterocyclyl containing from 1 to 4 heteroatomsindependently selected from O, N and S, —O—R^(b), C(O)NR^(b)R^(c),—NR^(b)R^(c), —NR^(c)C(O)—R^(b), —C(O)NR^(b)R^(c), —NR^(c)S(O₀₋₂)R^(b),—S(O₀₋₂)R^(b), wherein R^(b) and R^(c) are as defined in claim
 1. 3. Acompound according to claim 2 wherein R⁹ is a C₁₋₆alkyl groupsubstituted by pyridyl, thienyl, piperidinyl, imidazolyl, triazolyl,thiazolyl, pyrrolidinyl, piperazinyl, morpholinyl, imidazolinyl,benztriazolyl, benzimidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl,oxazolyl, furanyl, pyrrolyl, 1,3-dioxolanyl or 2-azetinyl, each of whichis optionally substituted as defined in claim
 2. 4. A compound accordingto claim 1 wherein the structure N(R⁹R¹⁰) represents anoptionally-substituted 3- to 10 membered heterocyclic ring optionallycontaining from 1 to 3 further heteroatoms independently selected fromO, N and S.
 5. A compound according to claim 4 wherein the 3- to 10membered heterocyclic ring is optionally substituted by one of moregroups selected from R¹⁵ wherein R¹⁵ represents the group R^(15a)-Z-wherein R^(15a) is selected from optionally substituted aryl, anoptionally substituted 3- to 10 membered heterocyclic ring or optionallysubstituted C₁₋₄alkyl and Z is selected from a a direct bond,—(CH₂)_(s1)—, —(CH₂)_(s1)—O—(CH₂)_(s2)—, —(CH₂)_(s1)—C(O)—(CH₂)_(s2)—,—(CH₂)_(s1)—S(O_(n))—(CH₂)_(s2)—, —(CH₂)_(s1)—N(R¹⁸)—(CH₂)_(s2)—,—(CH₂)_(s1)—C(O)N(R¹⁸)—(CH₂)_(s2)—, —(CH₂)_(s1)—N(R¹⁸)C(O)—(CH₂)_(s2)—,—(CH₂)_(s1)—N(R¹⁸)C(O)N(R¹⁸)—(CH₂)_(s2)—, —(CH₂)_(s1)—OC(O)—(CH₂)_(s2)—,—(CH₂)_(s1)—C(O)O—(CH₂)_(s2)—, —(CH₂)_(s1)—N(R¹⁸)C(O)O—(CH₂)_(s2)—,—(CH₂)_(s1)—OC(O)N(R¹⁸)—(CH₂)_(s2)—, —(CH₂)_(s1)—OS(O_(n))—(CH₂)_(s2)—,or —(CH₂)_(s1)—S(O_(n))—O—(CH₂)_(s2)—,—(CH₂)_(s1)—S(O)₂N(R¹⁸)—(CH₂)_(s2)—,—(CH₂)_(s1)—N(R¹⁸)S(O)₂—(CH₂)_(s2)—; wherein the —(CH₂)_(s1)— and—(CH₂)_(s2)— groups are independently optionally substituted by hydroxyor C₁₋₄alkyl and s1 and s2 are independently an integer from 0 to 2,wherein s1+s2 is less than or equal to 2 and R¹⁸ is selected fromhydrogen or C₁₋₄alkyl; wherein the optional substituents on aryl, aheterocyclic ring or C₁₋₄alkyl are selected from: hydroxy, amino, nitro,cyano, optionally-substituted aryl, optionally substituted 3- to8-membered heterocyclyl containing from 1 to 4 heteroatoms independentlyselected from O, N and S, —O—R^(g), —C(O)—R^(g), —C(O)NR^(g)R^(h),—NR^(g)R^(h), —NR^(h)C(O)—R^(g), —C(O)NR^(g)R^(h), —NR^(h)S(O₀₋₂)R^(g),—S(O₀₋₂)R^(g), wherein R^(g) and R^(g) are independently selected from:heterocyclyl, hydrogen and C₁₋₄alkyl optionally substituted withhydroxy, amino, N—C₁₋₄alkylamino, N,N-di-C₁₋₄alkylamino,HO—C₂₋₄alkyl-NH— or HO—C₂₋₄alkyl-N(C₁₋₄alkyl)-.
 6. A compound accordingto claim 5, wherein Z is selected from a direct bond or carbonyl.
 7. Acompound according to claim 1 wherein R⁵ is selected from a group offormula III-a , III-g, III-h, III-i or III-j:


8. A compound according to claim 1 wherein: (a) X represents N and R⁸represents cyano or —C(O)O—R^(b); wherein R^(b) is as defined in claim1, or (b) X represents N and R⁸ represents hydrogen.
 9. A compoundaccording to claim 1 preceding claims wherein R² is selected from anoptionally substituted monocyclic aromatic ring structure wherein theoptional substituents are selected from cyano, NR^(e)R^(f), optionallysubstituted C₁₋₈alkyl, optionally substituted C₁₋₈alkoxy or halo whereinR^(e) and R^(f) are independently selected from hydrogen, C₁₋₆alkyl oraryl.
 10. A compound according to claim 1 preceding claims wherein R¹ ishydrogen.
 11. A compound selected from:2-(1,1-dimethyl-2-oxo-2-azabicyclo[2.2.1]heptan-7-ylethyl)-4-[1S-methyl-2-(N′-isopropoxycarbonyl-3-pyrid-4-yl-pyrrolidin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole;2-(1,1-dimethyl-2-oxo-2-azabicyclo[2.2.1]heptan-7-ylethyl)-4-[2-(N′-isopropoxycarbonyl-3-pyrid-4-yl-pyrrolidin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole;2-(2-pyrrolidin-1-yl-1,1-dimethyl-2-oxoethyl)-4-[1S-methyl-2-(N′-isopropoxycarbonyl-3-pyrid-4-yl-pyrrolidin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole;2-(1,1-dimethyl-2-oxo-2-azabicyclo[2.2.1]heptan-7-ylethyl)-4-[1S-methyl-2-(N′-isopropoxycarbonyl-4-tetrahydropyran-4-yl-piperidin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole;2-(1,1-dimethyl-2-oxo-2-azabicyclo[2.2.1]heptan-7-ylethyl)-4-[1S-methyl-2-(3-pyrid-4-yl-pyrrolidin-1-ylcarbonyl)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole;2-(1,1-dimethyl-2-oxo-2-azabicyclo[2.2.1]heptan-7-ylethyl)-4-[1S-methyl-2-(N′-ethoxycarbonyl-3-pyrid-4-yl-pyrrolidin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrole;or a salt, pro-drug or solvate thereof.
 12. A pharmaceutical formulationcomprising a compound, or salt, pro-drug or solvate thereof, accordingto claim 1 and a pharmaceutically acceptable diluent or carrier.
 13. Amethod of antagonising gonadotropin releasing hormone activity, themethod comprising administering a compound according to claim 1, orsalt, pro-drug or solvate thereof, to a patient.
 14. A process ofproducing a compound, or salt, pro-drug or solvate thereof, according toclaim 1, wherein the process comprises a reaction step selected from anyone of steps (a) to (f): (a) Reaction of a compound of formula XXXII asfollows

(b) Cleavage of the cyano group of a compound of formula XXXIII in thepresence of acid to produce a compound of formula XXXIV

(c) Reaction of a compound of formula XXXV as follows

(d) Reaction of a compound of formula XXXVII as follows

(e) Reaction of a compound of formula XXXIX as follows

(f) to form a compound wherein X is nitrogen and Reaction of a compoundof formula XXXXI as follows

and thereafter if necessary: i) converting a compound of the Formula (I)into another compound of the Formula (I); ii) removing any protectinggroups; iii) forming a salt, pro-drug or solvate.